Search (autoimmun* OR arthritis OR lupus OR asthma OR psoria*) AND ((trif OR ticam-1 OR ticam1) OR (tirp OR tram OR ticam2 OR ticam-2) OR (myd-88 OR myd88)) Limits: Publication Date from 1994/01/01 to 2003/12/31 Entrez pubmed Results Items 1 - 16 of 16 1: Liu B et al. Cell surface expression of an...[PMID: 14668429] Related Articles, Gene, HomoloGene, UniGene, Nucleotide, Protein, GEO Profiles, Free in PMC, Cited in PMC, Books, LinkOut PMID- 14668429 OWN - NLM STAT- MEDLINE DA - 20031224 DCOM- 20040420 LR - 20041117 PUBM- Print-Electronic IS - 0027-8424 VI - 100 IP - 26 DP - 2003 Dec 23 TI - Cell surface expression of an endoplasmic reticulum resident heat shock protein gp96 triggers MyD88-dependent systemic autoimmune diseases. PG - 15824-9 AB - Heat shock proteins have been implicated as endogenous activators for dendritic cells (DCs). Without tissue distress or death, these intracellular molecules are inaccessible to surface receptor(s) on DCs, possibly to avoid uncontrolled DC activation and breakdown of immunologic tolerance. We herein addressed this hypothesis in transgenic mice by enforcing cell surface expression of gp96, a ubiquitous heat shock protein of the endoplasmic reticulum. Although a pan-specific promoter is used for transgene expression, neither the expression level nor the tissue distribution of the endogenous gp96 was altered by this maneuver. However, cell surface gp96 induced significant DC activations and spontaneous lupus-like autoimmune diseases, even though the development/functions of lymphocytic compartments were unaltered. Using a bone marrow chimera approach, we further demonstrated that both DC activation and autoimmunity elicited by cell surface gp96 are dependent on the downstream adaptor protein MyD88 for signaling by Toll/IL-1 receptor family. Our study not only established the proinflammatory property of cell surface gp96 in vivo, but also suggested a chronic stimulation of DCs by gp96 as a pathway to initiate spontaneous autoimmune diseases. AD - Center for Immunotherapy of Cancer and Infectious Diseases, University of Connecticut School of Medicine, 263 Farmington Avenue, Farmington, CT 06030-1601, USA. FAU - Liu, Bei AU - Liu B FAU - Dai, Jie AU - Dai J FAU - Zheng, Hong AU - Zheng H FAU - Stoilova, Diliana AU - Stoilova D FAU - Sun, Shaoli AU - Sun S FAU - Li, Zihai AU - Li Z LA - eng GR - CA100191/CA/NCI GR - CA90337/CA/NCI PT - Journal Article DEP - 20031210 PL - United States TA - Proc Natl Acad Sci U S A JID - 7505876 RN - 0 (Antibodies, Antinuclear) RN - 0 (Antigens, Differentiation) RN - 0 (Antigens, Neoplasm) RN - 0 (Heat-Shock Proteins) RN - 0 (MyD88 protein) RN - 0 (Receptors, Immunologic) RN - 0 (sarcoma glycoprotein gp96 rejection antigens) SB - IM MH - Animals MH - Antibodies, Antinuclear/analysis MH - Antigens, Differentiation/*immunology MH - Antigens, Neoplasm/*genetics MH - Autoimmune Diseases/*immunology MH - B-Lymphocytes/immunology MH - Bone Marrow Cells/immunology MH - Bone Marrow Transplantation/immunology MH - Dendritic Cells/immunology MH - Endoplasmic Reticulum/immunology MH - Genotype MH - Heat-Shock Proteins/*genetics MH - Lupus Erythematosus, Systemic/immunology MH - Lymphocyte Culture Test, Mixed MH - Mice MH - Mice, Inbred C57BL MH - Mice, Knockout MH - Mice, Transgenic MH - Receptors, Immunologic/deficiency/*immunology MH - Research Support, U.S. Gov't, P.H.S. MH - T-Lymphocytes/immunology EDAT- 2003/12/12 05:00 MHDA- 2004/04/21 05:00 PHST- 2003/12/10 [aheadofprint] AID - 10.1073/pnas.2635458100 [doi] AID - 2635458100 [pii] PST - ppublish SO - Proc Natl Acad Sci U S A 2003 Dec 23;100(26):15824-9. Epub 2003 Dec 10. DR -------------------------------------------------------------------------------- 2: Joosten LA et al. Toll-like receptor 2 pathway ...[PMID: 14634130] Related Articles, Gene, GENSAT, HomoloGene, Compound via MeSH, Substance via MeSH, UniGene, Nucleotide, Protein, GEO Profiles, Books, LinkOut PMID- 14634130 OWN - NLM STAT- MEDLINE DA - 20031124 DCOM- 20040301 LR - 20041117 PUBM- Print IS - 0022-1767 VI - 171 IP - 11 DP - 2003 Dec 1 TI - Toll-like receptor 2 pathway drives streptococcal cell wall-induced joint inflammation: critical role of myeloid differentiation factor 88. PG - 6145-53 AB - The IL-1R/Toll-like receptor (TLR) superfamily of receptors has a key role in innate immunity and inflammation. In this study, we report that streptococcal cell wall (SCW)-induced joint inflammation is predominantly dependent on TLR-2 signaling, since TLR-2-deficient mice were unable to develop either joint swelling or inhibition of cartilage matrix synthesis. Myeloid differentiation factor 88 (MyD88) is a Toll/IL-1R domain containing adaptor molecule known to have a central role in both IL-1R/IL-18R and TLR signaling. Mice deficient for MyD88 did not develop SCW-induced arthritis; both joint swelling and disturbance of cartilage chondrocyte anabolic function was completely abolished. Local levels of proinflammatory cytokines and chemokines in synovial tissue washouts were strongly reduced in MyD88-deficient mice. Histology confirmed the pivotal role of MyD88 in acute joint inflammation. TLR-2-deficient mice still allow influx of inflammatory cells into the joint cavity, although the number of cells was markedly reduced. No influx of inflammatory cells was seen in joints of MyD88-deficient mice. In addition, cartilage matrix proteoglycan loss was completely absent in MyD88 knockout mice. These findings clearly demonstrated that MyD88 is a key component in SCW-induced joint inflammation. Since agonists of the Toll-like pathway are abundantly involved in both septic and rheumatoid arthritis, targeting of MyD88 may be a novel therapy in inflammatory joint diseases. AD - Rheumatology Research Laboratory and Advanced Therapeutics, University Medical Center Nijmegen, Nijmegen, The Netherlands. l.joosten@reuma.umcn.nl FAU - Joosten, Leo A B AU - Joosten LA FAU - Koenders, Marije I AU - Koenders MI FAU - Smeets, Ruben L AU - Smeets RL FAU - Heuvelmans-Jacobs, Marleen AU - Heuvelmans-Jacobs M FAU - Helsen, Monique M A AU - Helsen MM FAU - Takeda, Kiyoshi AU - Takeda K FAU - Akira, Shizuo AU - Akira S FAU - Lubberts, Erik AU - Lubberts E FAU - van de Loo, Fons A J AU - van de Loo FA FAU - van den Berg, Wim B AU - van den Berg WB LA - eng PT - Journal Article PL - United States TA - J Immunol JID - 2985117R RN - 0 (Antigens, Differentiation) RN - 0 (Inflammation Mediators) RN - 0 (Interleukin-1) RN - 0 (Interleukin-18) RN - 0 (Membrane Glycoproteins) RN - 0 (MyD88 protein) RN - 0 (Proteoglycans) RN - 0 (Receptors, Cell Surface) RN - 0 (Receptors, Immunologic) RN - 0 (Receptors, Interleukin-1) RN - 0 (Toll-like receptors) RN - 0 (Tumor Necrosis Factor-alpha) SB - AIM SB - IM MH - Animals MH - Antigens, Differentiation/genetics/*physiology MH - Arthritis, Experimental/genetics/*immunology/metabolism/pathology MH - Cartilage, Articular/immunology/metabolism MH - Cell Wall/immunology MH - Down-Regulation/genetics/immunology MH - Inflammation Mediators/antagonists & inhibitors/metabolism MH - Interleukin-1/physiology MH - Interleukin-18/physiology MH - Male MH - Membrane Glycoproteins/biosynthesis/deficiency/genetics/*physiology MH - Mice MH - Mice, Inbred C57BL MH - Mice, Knockout MH - Multigene Family/immunology MH - Neutrophil Infiltration/genetics/immunology MH - Proteoglycans/immunology/metabolism MH - Receptors, Cell Surface/biosynthesis/deficiency/genetics/*physiology MH - Receptors, Immunologic/deficiency/genetics/*physiology MH - Receptors, Interleukin-1/antagonists & inhibitors/biosynthesis/physiology MH - Signal Transduction/genetics/immunology MH - Streptococcus pyogenes/*immunology MH - Tumor Necrosis Factor-alpha/physiology EDAT- 2003/11/25 05:00 MHDA- 2004/03/03 05:00 PST - ppublish SO - J Immunol 2003 Dec 1;171(11):6145-53. PR -------------------------------------------------------------------------------- 3: Akdis CA et al. Inhibition of T helper 2-type...[PMID: 14515255] Related Articles, Substance via MeSH, Cited in PMC, Books, LinkOut PMID- 14515255 OWN - NLM STAT- MEDLINE DA - 20030929 DCOM- 20031107 LR - 20041117 PUBM- Print IS - 0014-2980 VI - 33 IP - 10 DP - 2003 Oct TI - Inhibition of T helper 2-type responses, IgE production and eosinophilia by synthetic lipopeptides. PG - 2717-26 AB - In allergy and asthma, the fine balance between the T helper (Th) 1, Th2 and T regulatory cytokine responses appears to be shifted towards Th2. Here, we report that synthetic lipopeptides which contain the typical lipid part of the lipoprotein of gram-negative bacteria stimulate a distinct regulatory cytokine pattern and inhibit several Th2 cell-related phenomena. The most potent analogue of synthetic lipopeptides, lipopeptide CGP 40774 (LP40) was not active in MyD88-deficient mice and stimulated Toll-like receptor (TLR)-2, but not TLR-4. LP40 potentiated the production of IFN-gamma and IL-10, but not IL-4 and IL-5 by human T cells. In addition, triggering of TLR-2 by lipopeptides promoted the in vitro differentiation of naive T cells towards IL-10- and IFN-gamma-producing T cells and suppressed IL-4 production by Th2 cells. Accordingly, LP40 inhibited IgE production induced by allergen, anti-IgD antibody, Nippostrongylus brasiliensis or murine acquired immunodeficiency virus. Furthermore, ovalbumin-induced lung eosinophilic inflammation was abolished and Schistosoma mansoni egg-induced granuloma size and eosinophil counts were suppressed in mice by LP40. These results demonstrate that stimulation of TLR-2 by lipopeptides represents a novel way for possible treatment of allergy and asthma by regulating the disrupted cytokine balance. AD - Swiss Institute of Allergy and Asthma Research, Davos, Switzerland. FAU - Akdis, Cezmi A AU - Akdis CA FAU - Kussebi, Fatimah AU - Kussebi F FAU - Pulendran, Bali AU - Pulendran B FAU - Akdis, Mubeccel AU - Akdis M FAU - Lauener, Roger P AU - Lauener RP FAU - Schmidt-Weber, Carsten B AU - Schmidt-Weber CB FAU - Klunker, Sven AU - Klunker S FAU - Isitmangil, Gulbu AU - Isitmangil G FAU - Hansjee, Natasha AU - Hansjee N FAU - Wynn, Thomas A AU - Wynn TA FAU - Dillon, Stephanie AU - Dillon S FAU - Erb, Peter AU - Erb P FAU - Baschang, Gerhard AU - Baschang G FAU - Blaser, Kurt AU - Blaser K FAU - Alkan, Sefik S AU - Alkan SS LA - eng GR - AI48638-01/AI/NIAID GR - DK57665-01/DK/NIDDK PT - Journal Article PL - Germany TA - Eur J Immunol JID - 1273201 RN - 0 (Allergens) RN - 0 (Anti-Allergic Agents) RN - 0 (Lipoproteins) RN - 130068-27-8 (Interleukin-10) RN - 187348-17-0 (Interleukin-12) RN - 37341-29-0 (Immunoglobulin E) RN - 82115-62-6 (Interferon Type II) SB - IM MH - Allergens/immunology MH - Animals MH - Anti-Allergic Agents/*pharmacology MH - Eosinophilia/*prevention & control MH - Female MH - Humans MH - Immunoglobulin E/*biosynthesis MH - Interferon Type II/biosynthesis MH - Interleukin-10/biosynthesis MH - Interleukin-12/biosynthesis MH - Lipoproteins/*pharmacology MH - Male MH - Mice MH - Mice, Inbred BALB C MH - Mice, Inbred C57BL MH - Research Support, U.S. Gov't, P.H.S. MH - Schistosoma mansoni/immunology MH - Th2 Cells/*drug effects/immunology EDAT- 2003/09/30 05:00 MHDA- 2003/11/08 05:00 AID - 10.1002/eji.200323329 [doi] PST - ppublish SO - Eur J Immunol 2003 Oct;33(10):2717-26. NR -------------------------------------------------------------------------------- 4: O'Neill LA. Therapeutic targeting of Toll...[PMID: 12901949] Related Articles, Books, LinkOut PMID- 12901949 OWN - NLM STAT- MEDLINE DA - 20030806 DCOM- 20040106 LR - 20041117 PUBM- Print IS - 1471-4892 VI - 3 IP - 4 DP - 2003 Aug TI - Therapeutic targeting of Toll-like receptors for inflammatory and infectious diseases. PG - 396-403 AB - Roles for Toll-like receptors (TLRs) are emerging in conditions such as sepsis syndrome, systemic lupus erythromatosis, rheumatoid arthritis and asthma, suggesting that the selective targeting of TLRs might be useful therapeutically. TLRs are defined by the presence of extracellular leucine-rich repeats and an intracellular Toll/interleukin-1 receptor domain, and play a role in host defence and inflammation. Signalling pathways activated by TLRs show remarkable similarity to those activated by the pro-inflammatory cytokine interleukin-1 (the receptor for which also has a Toll/interleukin-1 receptor domain), although adaptor proteins specific for certain TLRs are starting to emerge (e.g. Mal and Trif). The common signalling pathways used by all members of the TLR superfamily are being targeted, with drugs that block nuclear factor-kappaB and p38 mitogen-activated protein kinase in clinical development for diseases such as rheumatoid arthritis and psoriasis. As we learn more about TLR signal transduction, more options are presenting themselves for pharmacological targeting. AD - Cytokine Research Group, Department of Biochemistry, Trinity College Dublin, Ireland. laoneill@tcd.ie FAU - O'Neill, Luke A J AU - O'Neill LA LA - eng PT - Journal Article PT - Review PT - Review, Tutorial PL - England TA - Curr Opin Pharmacol JID - 100966133 RN - 0 (Membrane Glycoproteins) RN - 0 (Receptors, Cell Surface) RN - 0 (Receptors, Interleukin-1) RN - 0 (Toll-like receptors) RN - 0 (interleukin-1 receptor type I) SB - IM MH - Animals MH - Communicable Diseases/drug therapy/*immunology/metabolism MH - Drug Delivery Systems MH - Humans MH - Inflammation/drug therapy/*immunology/metabolism MH - Membrane Glycoproteins/chemistry/*metabolism MH - Protein Structure, Tertiary MH - Receptors, Cell Surface/chemistry/*metabolism MH - Receptors, Interleukin-1/chemistry/metabolism MH - Research Support, Non-U.S. Gov't MH - Signal Transduction RF - 52 EDAT- 2003/08/07 05:00 MHDA- 2004/01/07 05:00 AID - S1471489203000808 [pii] PST - ppublish SO - Curr Opin Pharmacol 2003 Aug;3(4):396-403. DR -------------------------------------------------------------------------------- 5: Cattan P et al. Destruction of conditional in...[PMID: 12739022] Related Articles, Substance via MeSH, Books, LinkOut PMID- 12739022 OWN - NLM STAT- MEDLINE DA - 20030509 DCOM- 20040122 LR - 20041117 PUBM- Print-Electronic IS - 0012-186X VI - 46 IP - 4 DP - 2003 Apr TI - Destruction of conditional insulinoma cell lines in NOD mice: a role for autoimmunity. PG - 504-10 AB - AIMS/HYPOTHESIS: betaTC-tet (H2(k)) is a conditional insulinoma cell line derived from transgenic mice expressing a tetracycline-regulated oncogene. Transgenic expression of several proteins implicated in the apoptotic pathways increase the resistance of betaTC-tet cells in vitro. We tested in vivo the sensitivity of the cells to rejection and the protective effect of genetic alterations in NOD mice. METHODS: betaTC-tet cells and genetically engineered lines expressing Bcl-2 (CDM3D), a dominant negative mutant of MyD88 or SOCS-1 were transplanted in diabetic female NOD mice or in male NOD mice with diabetes induced by high-dose streptozotocin. Survival of functional cell grafts in NOD-scid mice was also analyzed after transfer of splenocytes from diabetic NOD mice. Autoreactive T-cell hybridomas and splenocytes from diabetic NOD mice were stimulated by betaTC-tet cells. RESULTS: betaTC-tet cells and genetically engineered cell lines were all similarly rejected in diabetic NOD mice and in NOD-scid mice after splenocyte transfer. In 3- to 6-week-old male NOD mice treated with high-dose streptozotocin, the cells temporarily survived, in contrast with C57BL/6 mice treated with high-dose streptozotocin (indefinite survival) and untreated 3- to 6-week-old male NOD mice (rejection). The protective effect of high-dose streptozotocin was lost in older male NOD mice. betaTC-tet cells did not stimulate autoreactive T-cell hybridomas, but induced IL-2 secretion by splenocytes from diabetic NOD mice. CONCLUSION/INTERPRETATION: The autoimmune process seems to play an important role in the destruction of betaTC-tet cells in NOD mice. Genetic manipulations intended at increasing the resistance of beta cells were inefficient. Similar approaches should be tested in vivo as well as in vitro. High dose streptozotocin influences immune rejection and should be used with caution. AD - INSERM U561, Groupe hospitalier Cochin-Saint Vincent de Paul, Paris, France. FAU - Cattan, P AU - Cattan P FAU - Rottembourg, D AU - Rottembourg D FAU - Cottet, S AU - Cottet S FAU - Tardivel, I AU - Tardivel I FAU - Dupraz, P AU - Dupraz P FAU - Thorens, B AU - Thorens B FAU - Boitard, C AU - Boitard C FAU - Carel, J C AU - Carel JC LA - eng PT - Journal Article DEP - 20030325 PL - Germany TA - Diabetologia JID - 0006777 RN - 0 (Interleukin-2) SB - IM MH - Animals MH - Autoimmunity/*immunology MH - *Cell Line, Tumor MH - Diabetes Mellitus, Experimental/immunology/metabolism MH - Female MH - Graft Rejection/immunology MH - Graft Survival/immunology MH - Hybridomas/metabolism MH - Insulinoma/*immunology/metabolism MH - Interleukin-2/pharmacokinetics MH - Mice MH - Mice, Inbred C57BL MH - Mice, Inbred NOD/*immunology MH - Research Support, Non-U.S. Gov't MH - Spleen/metabolism/secretion MH - Transplants EDAT- 2003/05/10 05:00 MHDA- 2004/01/24 05:00 PHST- 2002/08/06 [received] PHST- 2002/12/04 [revised] PHST- 2003/03/25 [aheadofprint] AID - 10.1007/s00125-003-1062-3 [doi] PST - ppublish SO - Diabetologia 2003 Apr;46(4):504-10. Epub 2003 Mar 25. DR -------------------------------------------------------------------------------- 6: Choe JY et al. Interleukin 1 receptor depend...[PMID: 12591910] Related Articles, Substance via MeSH, Cited in PMC, Books, LinkOut PMID- 12591910 OWN - NLM STAT- MEDLINE DA - 20030219 DCOM- 20030320 LR - 20041117 PUBM- Print IS - 0022-1007 VI - 197 IP - 4 DP - 2003 Feb 17 TI - Interleukin 1 receptor dependence of serum transferred arthritis can be circumvented by toll-like receptor 4 signaling. PG - 537-42 AB - Inflammatory arthritis is associated with the release of a network of key cytokines. In T cell receptor transgenic K/BxN mice interleukin (IL)-1 plays a key role in joint swelling and destruction, as suggested by the ability of anti-IL-1receptor (IL-1R) antibody treatment to delay the onset and slow the progression of this disease. This mechanism is dependent on the signaling pathway intermediary myeloid differentiation factor 88 (MyD88), such that neither IL-1R nor MyD88-deficient mice developed visually detectable synovitis after transfer of arthritogenic sera. The Toll-like receptors (TLRs) share the same signaling pathway through MyD88 as the IL-1R. The administration of a TLR-4 ligand, lipopolysaccharide, concomitant with arthritogenic serum in IL-1 receptor-deficient mice resulted in acute paw swelling, but not in MyD88-deficient mice. Also, serum transferred arthritis was not sustained in TLR-4 mutant mice compared with controls. These results suggest that innate immune functions via TLR-4 might perpetuate inflammatory mechanisms and bypass the need for IL-1 in chronic joint inflammation. AD - Division of Rheumatology, Allergy, and Immunology, and The Sam and Rose Stein Institute for Research on Aging, University of California, San Diego, La Jolla, CA 92093, USA. FAU - Choe, Jung-Yoon AU - Choe JY FAU - Crain, Brian AU - Crain B FAU - Wu, Sarah R AU - Wu SR FAU - Corr, Maripat AU - Corr M LA - eng PT - Journal Article PL - United States TA - J Exp Med JID - 2985109R RN - 0 (Antigens, Differentiation) RN - 0 (Drosophila Proteins) RN - 0 (Interleukin-1) RN - 0 (Membrane Glycoproteins) RN - 0 (MyD88 protein) RN - 0 (Receptors, Antigen, T-Cell) RN - 0 (Receptors, Cell Surface) RN - 0 (Receptors, Immunologic) RN - 0 (Receptors, Interleukin-1) RN - 0 (Toll-like receptors) SB - IM MH - Animals MH - Antigens, Differentiation/physiology MH - Arthritis, Rheumatoid/blood/*etiology MH - Disease Models, Animal MH - *Drosophila Proteins MH - Interleukin-1/physiology MH - Membrane Glycoproteins/*physiology MH - Mice MH - Mice, Inbred C3H MH - Mice, Inbred C57BL MH - Mice, Transgenic MH - Receptors, Antigen, T-Cell/genetics/physiology MH - Receptors, Cell Surface/*physiology MH - Receptors, Immunologic/physiology MH - Receptors, Interleukin-1/*physiology MH - Research Support, U.S. Gov't, P.H.S. EDAT- 2003/02/20 04:00 MHDA- 2003/03/21 04:00 PST - ppublish SO - J Exp Med 2003 Feb 17;197(4):537-42. DR -------------------------------------------------------------------------------- 7: Raschi E et al. Role of the MyD88 transductio...[PMID: 12531807] Related Articles, Gene, HomoloGene, Compound via MeSH, Substance via MeSH, UniGene, Nucleotide, Protein, GEO Profiles, Cited in PMC, Books, LinkOut PMID- 12531807 OWN - NLM STAT- MEDLINE DA - 20030422 DCOM- 20030620 LR - 20041117 PUBM- Print-Electronic IS - 0006-4971 VI - 101 IP - 9 DP - 2003 May 1 TI - Role of the MyD88 transduction signaling pathway in endothelial activation by antiphospholipid antibodies. PG - 3495-500 AB - Antiphospholipid syndrome (APS) is an autoimmune disease characterized by the persistent presence of antiphospholipid antibodies (aPLs) and recurrent thrombosis or fetal loss. The thrombophilic state has been partially related to the induction of a proinflammatory and procoagulant endothelial cell (EC) phenotype induced by anti-beta(2)-glycoprotein I (beta(2)-GPI) antibodies that bind beta(2)-GPI expressed on the EC surface. Anti-beta(2)-GPI antibody binding has been shown to induce nuclear factor-kappa B (NF-kappa B) translocation leading to a proinflammatory EC phenotype similar to that elicited by interaction with microbial products (lipopolysaccharide [LPS]) and proinflammatory cytokines (interleukin 1 beta [IL-1 beta], tumor necrosis factor alpha [TNF-alpha]). However, the upstream signaling events are not characterized yet. To investigate the endothelial signaling cascade activated by anti-beta(2)-GPI antibodies, we transiently cotransfected immortalized human microvascular endothelial cells (HMEC-1) with dominant-negative constructs of different components of the pathway (Delta TRAF2, Delta TRAF6, Delta MyD88) together with reporter genes (NF-kappa B luciferase and pCMV-beta-galactosidase). Results showed that both human anti-beta(2)-GPI IgM monoclonal antibodies as well as polyclonal affinity-purified anti-beta(2)-GPI IgG display a signaling cascade comparable to that activated by LPS or IL-1. Delta TRAF6 and Delta MyD88 significantly abrogate antibody-induced as well as IL-1- or LPS-induced NF-kappa B activation, whereas Delta TRAF2 (involved in NF-kappa B activation by TNF) does not affect it. Moreover, anti- beta(2)-GPI antibodies and LPS followed the same time kinetic of IL-1 receptor-activated kinase (IRAK) phosphorylation, suggesting an involvement of the toll-like receptor (TLR) family. Our findings demonstrate that anti-beta(2)-GPI antibodies react with their antigen likely associated to a member of the TLR/IL-1 receptor family on the EC surface and directly induce activation. AD - Istituto di Ricovero e Aura a Carattere Scientifico Istituto Auxologico Italiano, Allergy and Clinical Immunology Unit, Department of Internal Medicine, University of Milan, Italy. FAU - Raschi, Elena AU - Raschi E FAU - Testoni, Cinzia AU - Testoni C FAU - Bosisio, Daniela AU - Bosisio D FAU - Borghi, Maria O AU - Borghi MO FAU - Koike, Takao AU - Koike T FAU - Mantovani, Alberto AU - Mantovani A FAU - Meroni, Pier Luigi AU - Meroni PL LA - eng PT - Journal Article DEP - 20030116 PL - United States TA - Blood JID - 7603509 RN - 0 (Antibodies, Antiphospholipid) RN - 0 (Antibodies, Monoclonal) RN - 0 (Antigens, Differentiation) RN - 0 (E-Selectin) RN - 0 (Glycoproteins) RN - 0 (Lipopolysaccharides) RN - 0 (MyD88 protein) RN - 0 (NF-kappa B) RN - 0 (Proteins) RN - 0 (Receptors, Immunologic) RN - 0 (Recombinant Fusion Proteins) RN - 0 (TNF Receptor-Associated Factor 2) RN - 0 (TNF Receptor-Associated Factor 6) RN - 0 (beta 2-glycoprotein I) RN - EC 2.7.1.- (interleukin-1 receptor-associated kinase) RN - EC 2.7.1.37 (Protein Kinases) SB - AIM SB - IM MH - Adult MH - Antibodies, Antiphospholipid/immunology/*pharmacology MH - Antibodies, Monoclonal/immunology/*pharmacology MH - Antigens, Differentiation/genetics/*physiology MH - Antiphospholipid Syndrome/complications/immunology MH - Cell Line, Transformed MH - E-Selectin/biosynthesis/genetics MH - Endothelium, Vascular/*immunology MH - Female MH - Gene Deletion MH - Gene Expression Regulation/drug effects MH - Genes, Reporter MH - Glycoproteins/*immunology MH - Humans MH - Lipopolysaccharides/pharmacology MH - NF-kappa B/metabolism MH - Phosphorylation MH - Protein Kinases/metabolism MH - Protein Processing, Post-Translational MH - Proteins/genetics/physiology MH - Receptors, Immunologic/genetics/*physiology MH - Recombinant Fusion Proteins/physiology MH - Research Support, Non-U.S. Gov't MH - Signal Transduction/*physiology MH - TNF Receptor-Associated Factor 2 MH - TNF Receptor-Associated Factor 6 MH - Thrombophilia/etiology/immunology MH - Transfection EDAT- 2003/01/18 04:00 MHDA- 2003/06/21 05:00 PHST- 2003/01/16 [aheadofprint] AID - 10.1182/blood-2002-08-2349 [doi] AID - 2002-08-2349 [pii] PST - ppublish SO - Blood 2003 May 1;101(9):3495-500. Epub 2003 Jan 16. DR -------------------------------------------------------------------------------- 8: Jensen BS et al. The Ca2+-activated K+ channel...[PMID: 12472376] Related Articles, Books, LinkOut PMID- 12472376 OWN - NLM STAT- In-Process DA - 20021210 PUBM- Print IS - 1744-7631 VI - 6 IP - 6 DP - 2002 Dec TI - The Ca2+-activated K+ channel of intermediate conductance:a possible target for immune suppression. PG - 623-36 AB - The intermediate conductance Ca2+-activated K+ (IK) channel is distinguished from the functionally related Ca2+-activated K+ channels of smaller and larger unitary conductance by its molecular structure, pharmacology, tissue distribution and physiology. Like many K+ channels, IK is an assembly of four identical subunits each spanning the membrane six times and each contributing equally to the K+ selectivity pore positioned centrally in the complex. The IK channel gains its high sensitivity to intracellular Ca2+ from tightly bound calmodulin, and its activity is independent of the membrane potential. Several toxins including charybdotoxin and the more selective mutant, Glu32-charybdotoxin, maurotoxin and stichodactyla toxin potently block IK channels. Among blockers of the IK channel are also several small organic molecules including the antimycotic clotrimazole and the close analogues TRAM-34 and ICA-17043, as well as the antihypertensive, nitrendipine. The IK channel is distributed in peripheral tissues, including secretory epithelia and blood cells, but it appears absent from neuronal and muscle tissue. An important physiological role of the IK channel is to help maintain large electrical gradients for the sustained transport of ions such as Ca2+ influx that controls T lymphocyte (T cell) proliferation. In this review, special attention is given to an analysis of the use of IK blockers as potential immunosuppressants for the treatment of autoimmune disorders such as rheumatoid arthritis, inflammatory bowel disease and multiple sclerosis. AD - Section of Ion Channel Pharmacology, NeuroSearch A/S, 93 Pederstrupvej, DK-2750 Ballerup, Denmark. bsj@neurosearch.dk FAU - Jensen, B S AU - Jensen BS FAU - Hertz, M AU - Hertz M FAU - Christophersen, P AU - Christophersen P FAU - Madsen, L S AU - Madsen LS LA - eng PT - Journal Article PL - England TA - Expert Opin Ther Targets JID - 101127833 SB - IM EDAT- 2002/12/11 04:00 MHDA- 2002/12/11 04:00 PST - ppublish SO - Expert Opin Ther Targets 2002 Dec;6(6):623-36. NR -------------------------------------------------------------------------------- 9: Bozinovski S et al. Granulocyte/macrophage-colony...[PMID: 12208854] Related Articles, Gene, HomoloGene, Compound via MeSH, Substance via MeSH, UniGene, Nucleotide, Protein, GEO Profiles, Cited in PMC, Books, LinkOut PMID- 12208854 OWN - NLM STAT- MEDLINE DA - 20021104 DCOM- 20030206 LR - 20050111 PUBM- Print-Electronic IS - 0021-9258 VI - 277 IP - 45 DP - 2002 Nov 8 TI - Granulocyte/macrophage-colony-stimulating factor (GM-CSF) regulates lung innate immunity to lipopolysaccharide through Akt/Erk activation of NFkappa B and AP-1 in vivo. PG - 42808-14 AB - The lung innate immune response to lipopolysaccharide (LPS) coordinates cellular inflammation, mediator, and protease release essential for host defense but deleterious in asthma, chronic obstructive pulmonary disease, and cystic fibrosis. In vitro, LPS signals to the transcription factors NFkappaB via TLR4, MyD88, and IL-1R-associated kinase (IRAK), to AP-1 by mitogen-activated protein (MAP) kinases, and via an alternate route in IRAK-deficient mice, but the in vivo lung signaling pathway(s) are not understood. We investigated the role of Akt and Erk1/2 as LPS intensely stimulates granulocyte/macrophage-colony-stimulating factor (GM-CSF) release, and neutralizing GM-CSF profoundly suppressed LPS-induced inflammation, suppressed expression and activity of lung proteases, significantly reduced GM-CSF and tumor necrosis factor alpha (TNFalpha) mRNA expression, and dampened nuclear localization of both NFkappaB (p50/65) and AP-1. LPS markedly activated Akt and Erk1/2, but not p38, in a GM-CSF-dependent manner in direct temporal association with NFkappaB and AP-1 activation. Pharmacological inhibition of Akt or Erk activation in LPS-treated tracheal explants ex vivo inhibited the release of GM-CSF. These data implicate GM-CSF-dependent activation of Akt in the amplification of this response and demonstrate the role of Erks rather than p38 in lung LPS inflammatory responses. Inhibition of GM-CSF may be of therapeutic benefit in inflammatory diseases in which LPS contributes to lung damage. AD - Arthritis and Inflammation Research Center, Department of Medicine, Cooperative Research Center (CRC) for Chronic Inflammatory Diseases, Royal Melbourne Hospital, The University of Melbourne, Parkville, VIC 3010, Australia. FAU - Bozinovski, Steven AU - Bozinovski S FAU - Jones, Jessica E AU - Jones JE FAU - Vlahos, Ross AU - Vlahos R FAU - Hamilton, John A AU - Hamilton JA FAU - Anderson, Gary P AU - Anderson GP LA - eng PT - Journal Article DEP - 20020902 PL - United States TA - J Biol Chem JID - 2985121R RN - 0 (Androstadienes) RN - 0 (Antibodies, Monoclonal) RN - 0 (DNA Primers) RN - 0 (Enzyme Inhibitors) RN - 0 (Lipopolysaccharides) RN - 0 (MAP Kinase Signaling System) RN - 0 (NF-kappa B) RN - 0 (Proto-Oncogene Proteins) RN - 0 (Transcription Factor AP-1) RN - 0 (Tumor Necrosis Factor-alpha) RN - 19545-26-7 (wortmannin) RN - 83869-56-1 (Granulocyte-Macrophage Colony-Stimulating Factor) RN - EC 2.7.1.112 (Protein-Tyrosine Kinase) RN - EC 2.7.1.37 (Mitogen-Activated Protein Kinases) RN - EC 2.7.1.37 (Protein-Serine-Threonine Kinases) RN - EC 2.7.1.37 (proto-oncogene proteins c-akt) RN - EC 3.4.24.35 (Gelatinase B) SB - IM MH - Administration, Intranasal MH - Androstadienes/pharmacology MH - Animals MH - Antibodies, Monoclonal/pharmacology MH - Base Sequence MH - Bronchoalveolar Lavage Fluid/chemistry MH - Cell Nucleus/drug effects/physiology MH - DNA Primers MH - Enzyme Activation MH - Enzyme Inhibitors/pharmacology MH - Gelatinase B/metabolism MH - Gene Expression Regulation/immunology MH - Granulocyte-Macrophage Colony-Stimulating Factor/immunology/*pharmacology MH - Instillation, Drug MH - Kinetics MH - Lipopolysaccharides/administration & dosage/immunology/*toxicity MH - Lung/drug effects/*immunology MH - MAP Kinase Signaling System/drug effects/*physiology MH - Male MH - Mice MH - Mice, Inbred BALB C MH - Mitogen-Activated Protein Kinases/*metabolism MH - NF-kappa B/*genetics MH - *Protein-Serine-Threonine Kinases MH - Protein-Tyrosine Kinase/metabolism MH - Proto-Oncogene Proteins/*metabolism MH - Research Support, Non-U.S. Gov't MH - Transcription Factor AP-1/*genetics MH - Tumor Necrosis Factor-alpha/metabolism EDAT- 2002/09/05 10:00 MHDA- 2003/02/07 04:00 PHST- 2002/09/02 [aheadofprint] AID - 10.1074/jbc.M207840200 [doi] AID - M207840200 [pii] PST - ppublish SO - J Biol Chem 2002 Nov 8;277(45):42808-14. Epub 2002 Sep 2. NR -------------------------------------------------------------------------------- 10: Leadbetter EA et al. Chromatin-IgG complexes activ...[PMID: 11948342] Related Articles, Substance via MeSH, OMIM, Cited in PMC, Cited in Books, Books, LinkOut PMID- 11948342 OWN - NLM STAT- MEDLINE DA - 20020411 DCOM- 20020517 LR - 20041117 PUBM- Print IS - 0028-0836 VI - 416 IP - 6881 DP - 2002 Apr 11 TI - Chromatin-IgG complexes activate B cells by dual engagement of IgM and Toll-like receptors. PG - 603-7 AB - Autoreactive B cells are present in the lymphoid tissues of healthy individuals, but typically remain quiescent. When this homeostasis is perturbed, the formation of self-reactive antibodies can have serious pathological consequences. B cells expressing an antigen receptor specific for self-immunoglobulin-gamma (IgG) make a class of autoantibodies known as rheumatoid factor (RF). Here we show that effective activation of RF+ B cells is mediated by IgG2a-chromatin immune complexes and requires the synergistic engagement of the antigen receptor and a member of the MyD88-dependent Toll-like receptor (TLR) family. Inhibitor studies implicate TLR9. These data establish a critical link between the innate and adaptive immune systems in the development of systemic autoimmune disease and explain the preponderance of autoantibodies reactive with nucleic acid-protein particles. The unique features of this dual-engagement pathway should facilitate the development of therapies that specifically target autoreactive B cells. AD - Department of Microbiology, Boston University School of Medicine, Boston, Massachusetts 02118, USA. FAU - Leadbetter, Elizabeth A AU - Leadbetter EA FAU - Rifkin, Ian R AU - Rifkin IR FAU - Hohlbaum, Andreas M AU - Hohlbaum AM FAU - Beaudette, Britte C AU - Beaudette BC FAU - Shlomchik, Mark J AU - Shlomchik MJ FAU - Marshak-Rothstein, Ann AU - Marshak-Rothstein A LA - eng PT - Journal Article PL - England TA - Nature JID - 0410462 RN - 0 (Antigen-Antibody Complex) RN - 0 (Antigens, Differentiation) RN - 0 (Chromatin) RN - 0 (DNA-Binding Proteins) RN - 0 (Drosophila Proteins) RN - 0 (Immunoglobulin G) RN - 0 (Immunoglobulin M) RN - 0 (Membrane Glycoproteins) RN - 0 (MyD88 protein) RN - 0 (Receptors, Cell Surface) RN - 0 (Receptors, Complement 3b) RN - 0 (Receptors, Complement 3d) RN - 0 (Receptors, Immunologic) RN - 0 (Toll-like receptor 9) RN - 0 (Toll-like receptors) RN - 9009-79-4 (Rheumatoid Factor) RN - EC 3.1.21.1 (Deoxyribonuclease I) SB - IM CIN - Nature. 2002 Apr 11;416(6881):595-8. PMID: 11948338 MH - Animals MH - Antigen-Antibody Complex MH - Antigens, Differentiation/metabolism MH - B-Lymphocytes/*immunology MH - Chromatin/*immunology MH - DNA-Binding Proteins/antagonists & inhibitors/metabolism MH - Deoxyribonuclease I/metabolism MH - *Drosophila Proteins MH - Immunoglobulin G/*immunology MH - Immunoglobulin M/*immunology MH - *Lymphocyte Activation MH - Membrane Glycoproteins/*metabolism MH - Mice MH - Receptors, Cell Surface/antagonists & inhibitors/*metabolism MH - Receptors, Complement 3b/deficiency/immunology MH - Receptors, Complement 3d/deficiency/immunology MH - Receptors, Immunologic/metabolism MH - Research Support, Non-U.S. Gov't MH - Research Support, U.S. Gov't, P.H.S. MH - Rheumatoid Factor/*immunology MH - Signal Transduction EDAT- 2002/04/12 10:00 MHDA- 2002/05/23 10:01 AID - 10.1038/416603a [doi] AID - 416603a [pii] PST - ppublish SO - Nature 2002 Apr 11;416(6881):603-7. DR -------------------------------------------------------------------------------- 11: Asea A et al. Novel signal transduction pat...[PMID: 11836257] Related Articles, Gene, UniGene, Nucleotide, Protein, GEO Profiles, Cited in PMC, Books, LinkOut PMID- 11836257 OWN - NLM STAT- MEDLINE DA - 20020422 DCOM- 20020531 LR - 20041117 PUBM- Print-Electronic IS - 0021-9258 VI - 277 IP - 17 DP - 2002 Apr 26 TI - Novel signal transduction pathway utilized by extracellular HSP70: role of toll-like receptor (TLR) 2 and TLR4. PG - 15028-34 AB - Recent studies have initiated a paradigm shift in the understanding of the function of heat shock proteins (HSP). It is now clear that HSP can and do exit mammalian cells, interact with cells of the immune system, and exert immunoregulatory effects. We recently demonstrated that exogenously added HSP70 possesses potent cytokine activity, with the ability to bind with high affinity to the plasma membrane, elicit a rapid intracellular Ca(2+) flux, activate NF-kappaB, and up-regulate the expression of pro-inflammatory cytokines in human monocytes. Here for the first time, we report that HSP70-induced proinflammatory cytokine production is mediated via the MyD88/IRAK/NF-kappaB signal transduction pathway and that HSP70 utilizes both TLR2 (receptor for Gram-positive bacteria) and TLR4 (receptor for Gram-negative bacteria) to transduce its proinflammatory signal in a CD14-dependent fashion. These studies now pave the way for the development of highly effective pharmacological or molecular tools that will either up-regulate or suppress HSP70-induced functions in conditions where HSP70 effects are desirable (cancer) or disorders where HSP70 effects are undesirable (arthritis and arteriosclerosis). AD - Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA. FAU - Asea, Alexzander AU - Asea A FAU - Rehli, Michael AU - Rehli M FAU - Kabingu, Edith AU - Kabingu E FAU - Boch, Jason A AU - Boch JA FAU - Bare, Olivia AU - Bare O FAU - Auron, Philip E AU - Auron PE FAU - Stevenson, Mary Ann AU - Stevenson MA FAU - Calderwood, Stuart K AU - Calderwood SK LA - eng GR - AI44122/AI/NIAID GR - CA31303/CA/NCI GR - CA47404/CA/NCI GR - CA50642/CA/NCI GR - CA68544/CA/NCI GR - CA77465/CA/NCI PT - Journal Article DEP - 20020208 PL - United States TA - J Biol Chem JID - 2985121R RN - 0 (Drosophila Proteins) RN - 0 (Heat-Shock Proteins 70) RN - 0 (Membrane Glycoproteins) RN - 0 (NF-kappa B) RN - 0 (Receptors, Cell Surface) RN - 0 (Toll-like receptors) SB - IM MH - Cell Line MH - *Drosophila Proteins MH - Heat-Shock Proteins 70/*metabolism MH - Humans MH - Membrane Glycoproteins/*physiology MH - NF-kappa B/genetics/metabolism MH - Promoter Regions (Genetics) MH - Receptors, Cell Surface/*physiology MH - Research Support, U.S. Gov't, P.H.S. MH - *Signal Transduction/physiology EDAT- 2002/02/12 10:00 MHDA- 2002/06/01 10:01 PHST- 2002/02/08 [aheadofprint] AID - 10.1074/jbc.M200497200 [doi] AID - M200497200 [pii] PST - ppublish SO - J Biol Chem 2002 Apr 26;277(17):15028-34. Epub 2002 Feb 8. DR -------------------------------------------------------------------------------- 12: Beeton C et al. Selective blockade of T lymph...[PMID: 11717451] Related Articles, Compound via MeSH, Substance via MeSH, Free in PMC, Cited in PMC, Books, LinkOut PMID- 11717451 OWN - NLM STAT- MEDLINE DA - 20011121 DCOM- 20020108 LR - 20041117 PUBM- Print IS - 0027-8424 VI - 98 IP - 24 DP - 2001 Nov 20 TI - Selective blockade of T lymphocyte K(+) channels ameliorates experimental autoimmune encephalomyelitis, a model for multiple sclerosis. PG - 13942-7 AB - Adoptive transfer experimental autoimmune encephalomyelitis (AT-EAE), a disease resembling multiple sclerosis, is induced in rats by myelin basic protein (MBP)-activated CD4(+) T lymphocytes. By patch-clamp analysis, encephalitogenic rat T cells stimulated repeatedly in vitro expressed a unique channel phenotype ("chronically activated") with large numbers of Kv1.3 voltage-gated channels (approximately 1500 per cell) and small numbers of IKCa1 Ca(2+)-activated K(+) channels (approximately 50-120 per cell). In contrast, resting T cells displayed 0-10 Kv1.3 and 10-20 IKCa1 channels per cell ("quiescent" phenotype), whereas T cells stimulated once or twice expressed approximately 200 Kv1.3 and approximately 350 IKCa1 channels per cell ("acutely activated" phenotype). Consistent with their channel phenotype, [(3)H]thymidine incorporation by MBP-stimulated chronically activated T cells was suppressed by the peptide ShK, a blocker of Kv1.3 and IKCa1, and by an analog (ShK-Dap(22)) engineered to be highly specific for Kv1.3, but not by a selective IKCa1 blocker (TRAM-34). The combination of ShK-Dap(22) and TRAM-34 enhanced the suppression of MBP-stimulated T cell proliferation. Based on these in vitro results, we assessed the efficacy of K(+) channel blockers in AT-EAE. Specific and simultaneous blockade of the T cell channels by ShK or by a combination of ShK-Dap(22) plus TRAM-34 prevented lethal AT-EAE. Blockade of Kv1.3 alone with ShK-Dap(22), but not of IKCa1 with TRAM-34, was also effective. When administered after the onset of symptoms, ShK or the combination of ShK-Dap(22) plus TRAM-34 greatly ameliorated the clinical course of both moderate and severe AT-EAE. We conclude that selective targeting of Kv1.3, alone or with IKCa1, may provide an effective new mode of therapy for multiple sclerosis. AD - Laboratoire d'Immunologie, Faculte de Medecine, 13385 Marseille, France. FAU - Beeton, C AU - Beeton C FAU - Wulff, H AU - Wulff H FAU - Barbaria, J AU - Barbaria J FAU - Clot-Faybesse, O AU - Clot-Faybesse O FAU - Pennington, M AU - Pennington M FAU - Bernard, D AU - Bernard D FAU - Cahalan, M D AU - Cahalan MD FAU - Chandy, K G AU - Chandy KG FAU - Beraud, E AU - Beraud E LA - eng GR - MH59222/MH/NIMH GR - NS14069/NS/NINDS PT - Journal Article PL - United States TA - Proc Natl Acad Sci U S A JID - 7505876 RN - 0 (Calcium Channel Blockers) RN - 0 (Cnidarian Venoms) RN - 0 (IKCa1 channel) RN - 0 (Kv1.3 potassium channel) RN - 0 (Potassium Channel Blockers) RN - 0 (Potassium Channels) RN - 0 (Potassium Channels, Voltage-Gated) RN - 0 (Pyrazoles) RN - 0 (ShK neurotoxin) RN - 0 (TRAM 34) RN - 10028-17-8 (Tritium) RN - 50-89-5 (Thymidine) SB - IM MH - Animals MH - CD4-Positive T-Lymphocytes/cytology/drug effects/*metabolism MH - Calcium Channel Blockers/administration & dosage/pharmacokinetics/pharmacology MH - Cells, Cultured MH - Cnidarian Venoms/administration & dosage/pharmacokinetics/pharmacology MH - Disease Models, Animal MH - Encephalomyelitis, Autoimmune, Experimental/metabolism/*prevention & control MH - Female MH - Guinea Pigs MH - Isotope Labeling MH - Multiple Sclerosis/metabolism/*prevention & control MH - Phenotype MH - *Potassium Channel Blockers/administration & dosage/pharmacokinetics/pharmacology MH - Potassium Channels/*metabolism MH - *Potassium Channels, Voltage-Gated MH - Pyrazoles/administration & dosage/pharmacokinetics/pharmacology MH - Rats MH - Rats, Inbred Lew MH - Research Support, Non-U.S. Gov't MH - Research Support, U.S. Gov't, P.H.S. MH - Thymidine/metabolism MH - Tritium/metabolism EDAT- 2001/11/22 10:00 MHDA- 2002/01/10 10:01 AID - 10.1073/pnas.241497298 [doi] AID - 98/24/13942 [pii] PST - ppublish SO - Proc Natl Acad Sci U S A 2001 Nov 20;98(24):13942-7. NR -------------------------------------------------------------------------------- 13: Trif M et al. Liposomes as possible carrier...[PMID: 11395926] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 11395926 OWN - NLM STAT- MEDLINE DA - 20010608 DCOM- 20010712 LR - 20041117 PUBM- Print IS - 1535-3702 VI - 226 IP - 6 DP - 2001 Jun TI - Liposomes as possible carriers for lactoferrin in the local treatment of inflammatory diseases. PG - 559-64 AB - Liposomes prepared from naturally occurring biodegradable and nontoxic lipids are good candidates for local delivery of therapeutic agents. Treatment of arthritis by intra-articular administration of anti-inflammatory drugs encapsulated in liposomes prolongs the residence time of the drug in the joint. We have previously shown that intra-articular injection of human lactoferrin (hLf), a glycoprotein that possesses anti-inflammatory and antimicrobial activities, into mice with collagen-induced arthritis reduces inflammation. We have now investigated the possibility of using liposome-entrapped hLf as a delivery system to prolong hLf retention at sites of local inflammation such as the rheumatoid joint. Entrapment of hLf in negatively charged liposomes enhanced its accumulation in cultured human synovial fibroblasts from rheumatoid arthritis (RA) patients, compared with positively charged formulations or free protein. However, in the presence of synovial fluid, positively charged liposomes with entrapped hLf were more stable than the negatively charged formulations. In vivo experiments in mice with collagen-induced arthritis showed that the positive liposomes were more efficient in prolonging the residence time of hLf in the inflamed joint as compared with other liposomes. Thus, the amount of hLf retained in the joint after 2 hr was 60% of the injected dose in the case of positive liposomes and only 16% for negative pH-sensitive liposomes. The results suggest that entrapment of hLf in positively charged liposomes may modify its pharmacodynamic profile and be of therapeutic benefit in the treatment of RA and other local inflammatory conditions. AD - Institute of Biochemistry, Spl Independentei 296, 77700 Bucharest, Romania. mtrif@biochim.ro FAU - Trif, M AU - Trif M FAU - Guillen, C AU - Guillen C FAU - Vaughan, D M AU - Vaughan DM FAU - Telfer, J M AU - Telfer JM FAU - Brewer, J M AU - Brewer JM FAU - Roseanu, A AU - Roseanu A FAU - Brock, J H AU - Brock JH LA - eng PT - Journal Article PL - United States TA - Exp Biol Med (Maywood) JID - 100973463 RN - 0 (Anti-Inflammatory Agents, Non-Steroidal) RN - 0 (Lactoferrin) RN - 0 (Liposomes) RN - 9007-34-5 (Collagen) SB - IM MH - Animals MH - Anti-Inflammatory Agents, Non-Steroidal/*administration & dosage/metabolism MH - Arthritis, Rheumatoid/*drug therapy/metabolism MH - Cells, Cultured MH - Collagen/adverse effects MH - *Drug Delivery Systems MH - Drug Stability MH - Electrochemistry MH - Fibroblasts/metabolism MH - Humans MH - Injections MH - Lactoferrin/*administration & dosage/chemistry/metabolism MH - Liposomes MH - Male MH - Mice MH - Research Support, Non-U.S. Gov't MH - Synovial Fluid/metabolism MH - Synovial Membrane/cytology/metabolism MH - Tissue Distribution EDAT- 2001/06/09 10:00 MHDA- 2001/07/13 10:01 PST - ppublish SO - Exp Biol Med (Maywood) 2001 Jun;226(6):559-64. NR -------------------------------------------------------------------------------- 14: Dupraz P et al. Dominant negative MyD88 prote...[PMID: 10967106] Related Articles, Substance via MeSH, Books, LinkOut PMID- 10967106 OWN - NLM STAT- MEDLINE DA - 20001218 DCOM- 20010111 LR - 20050216 PUBM- Print IS - 0021-9258 VI - 275 IP - 48 DP - 2000 Dec 1 TI - Dominant negative MyD88 proteins inhibit interleukin-1beta /interferon-gamma -mediated induction of nuclear factor kappa B-dependent nitrite production and apoptosis in beta cells. PG - 37672-8 AB - Insulin-dependent diabetes mellitus is an autoimmune disease in which pancreatic islet beta cells are destroyed by a combination of immunological and inflammatory mechanisms. In particular, cytokine-induced production of nitric oxide has been shown to correlate with beta cell apoptosis and/or inhibition of insulin secretion. In the present study, we investigated whether the interleukin (IL)-1beta intracellular signal transduction pathway could be blocked by overexpression of dominant negative forms of the IL-1 receptor interacting protein MyD88. We show that overexpression of the Toll domain or the lpr mutant of MyD88 in betaTc-Tet cells decreased nuclear factor kappaB (NF-kappaB) activation upon IL-1beta and IL-1beta/interferon (IFN)-gamma stimulation. Inducible nitric oxide synthase mRNA accumulation and nitrite production, which required the simultaneous presence of IL-1beta and IFN-gamma, were also suppressed by approximately 70%, and these cells were more resistant to cytokine-induced apoptosis as compared with parental cells. The decrease in glucose-stimulated insulin secretion induced by IL-1beta and IFN-gamma was however not prevented. This was because these dysfunctions were induced by IFN-gamma alone, which decreased cellular insulin content and stimulated insulin exocytosis. These results demonstrate that IL-1beta is involved in inducible nitric oxide synthase gene expression and induction of apoptosis in mouse beta cells but does not contribute to impaired glucose-stimulated insulin secretion. Furthermore, our data show that IL-1beta cellular actions can be blocked by expression of MyD88 dominant negative proteins and, finally, that cytokine-induced beta cell secretory dysfunctions are due to the action of IFN-gamma. AD - Institute of Pharmacology and Toxicology, University of Lausanne, 27 Rue du Bugnon, 1005 Lausanne, Switzerland. FAU - Dupraz, P AU - Dupraz P FAU - Cottet, S AU - Cottet S FAU - Hamburger, F AU - Hamburger F FAU - Dolci, W AU - Dolci W FAU - Felley-Bosco, E AU - Felley-Bosco E FAU - Thorens, B AU - Thorens B LA - eng PT - Journal Article PL - UNITED STATES TA - J Biol Chem JID - 2985121R RN - 0 (Antigens, Differentiation) RN - 0 (Interleukin-1) RN - 0 (MyD88 protein) RN - 0 (NF-kappa B) RN - 0 (Nitrites) RN - 0 (RNA, Messenger) RN - 0 (Receptors, Immunologic) RN - 11061-68-0 (Insulin) RN - 82115-62-6 (Interferon Type II) RN - EC 1.14.13.39 (Nitric-Oxide Synthase) RN - EC 1.14.13.39 (inducible nitric oxide synthase) SB - IM MH - Animals MH - Antigens, Differentiation/genetics/*metabolism MH - *Apoptosis MH - Cell Line MH - Gene Expression Regulation, Enzymologic/genetics MH - Gene Transfer Techniques MH - Genes, Dominant MH - Hela Cells MH - Humans MH - Insulin/secretion MH - Interferon Type II/*pharmacology MH - Interleukin-1/*pharmacology MH - Islets of Langerhans/drug effects/*metabolism/pathology/secretion MH - Lentivirus/genetics MH - Mice MH - NF-kappa B/*metabolism MH - Nitric-Oxide Synthase/genetics MH - Nitrites/*metabolism MH - RNA, Messenger/genetics MH - *Receptors, Immunologic MH - Research Support, Non-U.S. Gov't MH - Signal Transduction EDAT- 2000/09/01 11:00 MHDA- 2001/02/28 10:01 AID - 10.1074/jbc.M005150200 [doi] AID - M005150200 [pii] PST - ppublish SO - J Biol Chem 2000 Dec 1;275(48):37672-8. DR -------------------------------------------------------------------------------- 15: Wulff H et al. Design of a potent and select...[PMID: 10884437] Related Articles, Compound via MeSH, Substance via MeSH, Free in PMC, Cited in PMC, Books, LinkOut PMID- 10884437 OWN - NLM STAT- MEDLINE DA - 20000810 DCOM- 20000810 LR - 20041117 PUBM- Print IS - 0027-8424 VI - 97 IP - 14 DP - 2000 Jul 5 TI - Design of a potent and selective inhibitor of the intermediate-conductance Ca2+-activated K+ channel, IKCa1: a potential immunosuppressant. PG - 8151-6 AB - The antimycotic clotrimazole, a potent inhibitor of the intermediate-conductance calcium-activated K(+) channel, IKCa1, is in clinical trials for the treatment of sickle cell disease and diarrhea and is effective in ameliorating the symptoms of rheumatoid arthritis. However, inhibition of cytochrome P450 enzymes by clotrimazole limits its therapeutic value. We have used a rational design strategy to develop a clotrimazole analog that selectively inhibits IKCa1 without blocking cytochrome P450 enzymes. A screen of 83 triarylmethanes revealed the pharmacophore for channel block to be different from that required for cytochrome P450 inhibition. The "IKCa1-pharmacophore" consists of a (2-halogenophenyl)diphenylmethane moiety substituted by an unsubstituted polar pi-electron-rich heterocycle (pyrazole or tetrazole) or a -CN group, whereas cytochrome P450 inhibition absolutely requires the imidazole ring. A series of pyrazoles, acetonitriles, and tetrazoles were synthesized and found to selectively block IKCa1. TRAM-34 (1-[(2-chlorophenyl)diphenylmethyl]-1H-pyrazole) inhibits the cloned and the native IKCa1 channel in human T lymphocytes with a K(d) of 20-25 nM and is 200- to 1,500-fold selective over other ion channels. Using TRAM-34, we show that blocking IKCa1 in human lymphocytes, in the absence of P450-inhibition, results in suppression of mitogen-stimulated [(3)H]thymidine incorporation of preactivated lymphocytes with EC(50)-values of 100 nM-1 microM depending on the donor. Combinations of TRAM-34 and cyclosporin A are more effective in suppressing lymphocyte mitogenesis than either compound alone. Our studies suggest that TRAM-34 and related compounds may hold therapeutic promise as immunosuppressants. AD - Department of Physiology and Biophysics, University of California, Irvine, CA 92697, USA. hwulff@uci.edu FAU - Wulff, H AU - Wulff H FAU - Miller, M J AU - Miller MJ FAU - Hansel, W AU - Hansel W FAU - Grissmer, S AU - Grissmer S FAU - Cahalan, M D AU - Cahalan MD FAU - Chandy, K G AU - Chandy KG LA - eng GR - MH59222/MH/NIMH GR - NS 14069/NS/NINDS PT - Journal Article PL - UNITED STATES TA - Proc Natl Acad Sci U S A JID - 7505876 RN - 0 (Calcium Channel Blockers) RN - 0 (Calcium Channels) RN - 0 (IKCa1 channel) RN - 0 (Immunosuppressive Agents) RN - 0 (Potassium Channels) RN - 0 (Pyrazoles) RN - 0 (TRAM 34) RN - 16561-29-8 (Tetradecanoylphorbol Acetate) RN - 23593-75-1 (Clotrimazole) RN - 56092-81-0 (Ionomycin) RN - 59865-13-3 (Cyclosporine) RN - 9035-51-2 (Cytochrome P-450 Enzyme System) SB - IM MH - Calcium Channel Blockers/*pharmacology MH - Calcium Channels/*drug effects MH - Clotrimazole/chemistry MH - Comparative Study MH - Cyclosporine/pharmacology MH - Cytochrome P-450 Enzyme System/drug effects MH - Drug Design MH - Drug Interactions MH - Electric Conductivity MH - Humans MH - Immunosuppressive Agents/*pharmacology MH - Ion Channel Gating MH - Ionomycin/pharmacology MH - Lymphocyte Activation/drug effects MH - *Potassium Channels MH - Pyrazoles/*pharmacology MH - Research Support, Non-U.S. Gov't MH - Research Support, U.S. Gov't, P.H.S. MH - Structure-Activity Relationship MH - T-Lymphocytes/drug effects MH - Tetradecanoylphorbol Acetate/pharmacology EDAT- 2000/07/08 11:00 MHDA- 2000/08/12 11:00 AID - 97/14/8151 [pii] PST - ppublish SO - Proc Natl Acad Sci U S A 2000 Jul 5;97(14):8151-6. NR -------------------------------------------------------------------------------- 16: Hudson DA. The surgically delayed uniped...[PMID: 8659945] Related Articles, Books, LinkOut PMID- 8659945 OWN - NLM STAT- MEDLINE DA - 19960730 DCOM- 19960730 LR - 20041117 PUBM- Print IS - 0148-7043 VI - 36 IP - 3 DP - 1996 Mar TI - The surgically delayed unipedicled TRAM flap for breast reconstruction. PG - 238-42; discussion 242-5 AB - Surgical delay is one method of enhancing the vascularity of the lower abdominal transverse rectus abdominis musculocutaneous (TRAM) flap. The outcome of 7 patients who underwent surgical delay (by ligating both superficial and deep inferior epigastric vessels bilaterally) a week prior to definitive TRAM flap elevation is described. Three patients were smokers, 3 were obese, and 1 was an asthmatic on medication. A satisfactory aesthetic result was achieved in all patients and the complications that occurred were minor. Two patients developed minor skin necrosis due to inadequate trimming of zone 4 on the contralateral side to the pedicle and there were 3 cases of fat necrosis, which occurred below Scarpa's fascia. Surgical delay is a useful technique of breast reconstruction. It allows the flap to be centered safely in the lower abdomen. In the high-risk patient, delay may prevent the need for microsurgery or the sacrifice of both recti. AD - Department of Plastic and Reconstructive Surgery, Groote Schuur Hospital, Cape Town, South Africa. FAU - Hudson, D A AU - Hudson DA LA - eng PT - Journal Article PL - UNITED STATES TA - Ann Plast Surg JID - 7805336 SB - IM CIN - Ann Plast Surg. 1996 Sep;37(3):342-3. PMID: 8883739 MH - Adult MH - Asthma/physiopathology MH - Breast Neoplasms/*surgery MH - Female MH - Graft Survival/physiology MH - Humans MH - Mammaplasty/*methods MH - Mastectomy, Modified Radical/*methods MH - Microsurgery/*methods MH - Middle Aged MH - Obesity/physiopathology MH - Regional Blood Flow/physiology MH - Retrospective Studies MH - Risk Factors MH - Smoking/adverse effects/physiopathology MH - Surgical Flaps/*methods/physiology MH - Treatment Outcome EDAT- 1996/03/01 MHDA- 1996/03/01 00:01 PST - ppublish SO - Ann Plast Surg 1996 Mar;36(3):238-42; discussion 242-5. NR