ARTICLE |
Correspondence to: Sven MüllerRöver, Centre for Cutaneous Research, St Bartholomew's and the Royal London School of Dentistry, QMW, 2 Newark Street, London E1 2AT, UK.
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Summary |
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Although the intercellular adhesion molecule-1 (ICAM-1) is recognized for its pivotal role in inflammation and immune responses, its role in developmental systems, such as the cyclic growth (anagen) and regression (catagen) of the hair follicle, remains to be explored. Here we demonstrate that ICAM-1 expression in murine skin is even more widespread and more developmentally regulated than was previously believed. In addition to endothelial cells, selected epidermal and follicular keratinocyte subpopulations, as well as interfollicular fibroblasts, express ICAM-1. Murine hair follicles express ICAM-1 only late during morphogenesis. Thereafter, morphologically identical follicles markedly differ in their ICAM-1 expression patterns, which become strikingly hair cycle-dependent in both intra- and extrafollicular skin compartments. Minimal ICAM-1 and leukocyte function-associated (LFA-1) protein and mRNA expression is observed during early anagen and maximal expression during late anagen and catagen. Keratinocytes of the distal outer root sheath, fibroblasts of the perifollicular connective tissue sheath, and perifollicular blood vessels exhibit maximal ICAM-1 immunoreactivity during catagen, which corresponds to changes of LFA-1 expression on perifollicular macrophages. Finally, ICAM-1-deficient mice display significant catagen acceleration compared to wild-type controls. Therefore, ICAM-1 upregulation is not limited to pathological situations but is also important for skin and hair follicle remodeling. Collectively, this suggests a new and apparently nonimmunological function for ICAM-1-related signaling in cutaneous biology. (J Histochem Cytochem 48:557568, 2000)
Key Words: depilation, ICAM-1-deficient mice, LFA-1, connective tissue sheath, hair cycle, catagen, mouse mutant, skin, adhesion receptor, adhesion molecules
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Introduction |
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The hair follicle (HF) is the only organ that for the entire lifetime of the mammalian organism shows cyclic switches between periods of massive epithelial cell proliferation and terminal differentiation (anagen), followed by rapid organ involution (catagen) and resting (telogen) (cf.
Typical examples for hair cycle-dependent skin remodeling are alterations of the skin and the HF immune system during synchronized HF cycling in mice, such as (a) changes in the number of intraepithelial T-cells and Langerhans cells, (b) changes in the follicular expression patterns of MHC Class I molecules, and (c) changes in contact sensitization responses (
It is reasonable to explore the possible role of cell adhesion molecules in this context. Among the cell adhesion molecules that may be relevant to hair biology (e.g., ICAM-1, NCAM, E- and P-cadherin, and ß1-integrins) (
During human fetal HF morphogenesis, ICAM-1 is transiently expressed on the outer cells of the hair germ (
The ICAM-1 ligand LFA-1 belongs to the ß2-integrin family and is expressed on most types of white blood cells (cf.
To examine the functional role of ICAM-1 expression in HF growth and regression, we have studied the immunohistological expression patterns of ICAM-1 and one of its key ligands, LFA-1, both during neonatal HF development in mice (
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Materials and Methods |
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Animals
Syngenic C57BL/6 mice (female, 69-week-old and 121-day-old neonatal mice; Charles River, Sulzfeld, Germany) as well as homozygous ICAM-1-deficient mice (female, 18-day-old Icamtm1Bay mutant strain; The Jackson Laboratory, Bar Harbor, ME) and age-matched wild-type controls (female 18-day-old, C57BL/6J; Jackson Laboratory) were used. These mice were housed in group cages, with 12-hr light periods, at the Virchow Hospital, Animal Facilities, Berlin, and were fed water and mouse chow ad libitum. Neonatal mice were examined because most pelage HFs in mice develop during the peri- and neonatal period (
Skin Specimens and Hair Cycle Induction
Dorsal skin was obtained from C57BL/6 mice in various stages of neonatal HF development and adolescent HF cycling (
At least six skin sections each were examined from five mice per hair cycle stage of the depilation-induced hair cycle and from days 121 after birth. Therefore, at least 100 different HFs obtained from five mice per stage of HF morphogenesis or cycling were analyzed. At least 10 skin sections and 100 HFs per mouse (= 700 HFs per group) each were examined from seven ICAM-1-deficient and seven corresponding wild-type mice.
Immunohistology
After extensive pilot assays had been performed to determine the most sensitive method for the detection of hair cycle-dependent ICAM-1 expression, the following protocol was found to yield optimal results. Sections were preabsorbed for 15 min at room temperature (RT) with 5% bovine and 5% mouse normal serum in Tris buffer (pH 7.6), followed by 15 min each with avidin and biotin blocking solution (Vecta-Stain kit; Vector Laboratories, Burlingame, CA) at RT. Every step was followed by washing for 15 min at RT (buffer was changed every 5 min). A specific biotinylated monoclonal hamster anti-mouse ICAM-1 antibody (clone 3E2,
The following specific rat anti-mouse antibodies were used at the dilution indicated: anti-LFA-antibody (clone 2D7, -T-cell receptor antibody (clone GL3,
Analysis of HF Regression in ICAM-1-deficient Mice and Wild-type Controls
Age- and sex-matched 18-day-old ICAM-1-deficient and wild-type littermates were used for the analysis of postnatal HF regression (catagen) (
Data Photodocumentation and Analysis
All immunoreactivity (IR) patterns were analyzed qualitatively and semiquantitatively in at least 100 HFs per stage of HF development or cycling derived from five different mice and were recorded in a computerized schematic representation of all stages of murine HF development and cycling (
RT-PCR
Semiquantitative RT-PCR analysis of ICAM-1, LFA-1, and of constitutively expressed ß-actin was performed using the previously described RT-PCR techniques (
The following sets of oligonucleotide primers were used:
Amplification was performed using taq polymerase (GIBCO; Grand Island, NY) over 36 cycles, using an automated thermal cycler (PerkinElmer Cetus; Norwalk, CT). Each cycle consisted of the following steps: denaturation at 94C (1 min), annealing at 55C (30 sec), and extension at 72C (1 min). PCR products were analyzed by agarose gel electrophoresis and enzymatic digestion using standard methods (
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Results |
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Constitutive ICAM-1 Expression Is a Late Event During Neonatal Mouse Skin and HF Morphogenesis
Using the methodology delineated above, no ICAM-1 IR could be detected in the developing HFs of neonatal mouse skin before Day 19 post partum. Unexpectedly, even the first stronger ICAM-1 expression on neonatal skin vasculature was not detected before Day 7 post partum (Fig 1A and Fig 1B), i.e., at a time when follicle development had far advanced and had reached Stage 57 of development (
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During this period of neonatal skin and HF development, no ICAM-1 IR was seen in any epithelial or mesenchymal follicle compartment, in the interfollicular epidermal, or in dermal cells (Fig 1A and Fig 1B). The first strong follicle-associated ICAM-1 IR appeared by Day 21 post partum on fibroblasts of the proximal connective tissue sheath of the HF (similar to adolescent catagen development; see corresponding Fig 2E2G), i.e., at a time when the HF had entered into its first catagen stage, thus initiating HF cycling.
ICAM-1 Expression Is Hair Cycle-dependent and Is Confined to Defined Skin Regions
When adolescent mouse skin was examined, it became apparent that, contrary to reports in the literature (
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In these mouse skin regions, the following observations on ICAM-1 IR were made. First, Several sections harvested at Day 1 post depilation (p.d.) [i.e., skin sections with all HFs in the earliest stage of synchronized, induced anagen development (anagen I)] showed a general epidermal increase in ICAM-1 IR compared to telogen (see Table 1), most likely as a response to the slight skin wounding associated with anagen induction by depilation (
The peri-infundibular region of the distal outer root sheath (piORS) showed a well-circumscribed ICAM-1 IR (Fig 2B), which changed substantially during the hair cycle (Table 1; Fig 3). Telogen skin only rarely exhibited follicles with a strongly ICAM-1+ piORS (defined here as at least half of the staining intensity of untreated telogen skin blood vessels), i.e., in 8% of all telogen follicles. The average percentage of strongly ICAM-1+ follicles decreased to 0% after anagen induction by depilation (p<0.05). Skin sections of Day 1 (anagen I) and Day 3 p.d. (anagen IIIII) showed only very faint ICAM-1 IR of the piORS, and no follicles at all were detected that displayed a strongly ICAM-1+ piORS. At Days 5 and 8 p.d. (anagen IIIV), ICAM-1 IR of the piORS was completely absent (Fig 2C). Follicles with ICAM-1+ piORS appeared to be fairly regularly distributed throughout the back skin and occurred most frequently in groups of two or three follicles with a strongly ICAM-1+ piORS. Unexpectedly, even topical application of 100% DMSO for 3 days, which causes a marked irritant dermatitis, induced only a faint upregulation of ICAM-1 IR in the piORS of anagen and telogen follicles. This was in striking contrast to the expected dramatic increase in dermal fibroblast ICAM-1 IR after DMSO treatment (not shown).
Compared to early and middle anagen (Days 18 p.d.), the percentage of follicles with a strongly ICAM-1+ piORS increased significantly during progressing later anagen and spontaneous HF entry into catagen (Fig 4A). In catagen VIIVIII, 85% of all follicles showed an ICAM-1+ piORS (Fig 2B, Fig 3, and Fig 4A), followed by the maximum at Day 20 p.d., when skin is composed of late catagen and the beginning of telogen development.
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In line with our previous reports (T-cells, nonclassical MHC Class I (MHC Ib) molecules (Qa-2a), and NLDC 145+ Langerhans cells in this region of the distal HF epithelium (not shown; for comparison see
Strikingly asymmetric ICAM-1 expression was detected on hair matrix keratinocytes in 19% of all induced anagen IVVI follicles, most pronouncedly in a unilateral cluster of ICAM-1+ hair matrix keratinocytes (Fig 2D, "M").
Starting from catagen III, several of the most proximally located fibroblasts of the proximal connective tissue sheath became strongly ICAM-1+. During the subsequent stages of catagen development, from the dermal papilla to the insertion of the sebaceous gland, a continous layer of ICAM-1+ mesenchymal cells became detectable surrounding the HF basement membrane (Fig 2E2G). The highest staining intensity was noted during catagen VI on cells of the proximal connective tissue sheath surrounding the epithelial strand of the regressing hair bulb (Fig 2E2G). One layer of fibroblasts directly adjacent to the glassy membrane of the epithelial strand of the regressing follicle exhibited ICAM-1 IR (Fig 2F and Fig 2G). On serial sections, these cells were strongly immunoreactive with the pan-reticular fibroblast marker ER-TR 7 but not with antibodies against E- or P-cadherin as markers of follicular keratinocytes (cf.
Interfollicular dermal fibroblasts showed a highly dynamic hair cycle-dependent pattern of ICAM-1 IR (Fig 2H, Fig 2I, and Fig 4B). In the interfollicular dermis, a small but significant decline of strongly ICAM-1+ fibroblasts was noted shortly after anagen induction (Day 1 p.d.), followed by a strong, significant increase (p<0.01) during anagen VI and catagen development (Days 1220 p.d.; cf. Fig 2I and Fig 4B) and another sharp decline to again reach telogen values (Day 25 p.d.; telogen; Fig 4B). This substantial upregulation of constitutive ICAM-1 IR on interfollicular dermal cells during the anagencatagen transformation was very similar to that seen in inflamed telogen skin after induction of an irritant contact dermatitis by DMSO treatment and was noted around all catagen follicles, irrespective of whether they had developed after depilation-induced or spontaneous anagen.
On endothelial cells of the plexus profundus, strong constitutive ICAM-1 IR was noted in all hair cycle stages (Fig 2J; Table 1). A gradually increasing number of perifollicular blood vessels displayed strong ICAM-1 IR during middle and late anagen (Fig 2J; Table 1). This was reminiscent of the upregulation of ICAM-1 IR observed on perifollicular blood vessels during the later stages of HF morphogenesis (Fig 1C), yet much stronger.
Control sections of 10-week-old mice that had developed anagen V and VI spontaneously displayed the same ICAM-1 IR patterns as seen during depilation-induced anagen V and VI. Again, the strongest cutaneous anti-ICAM-1 staining intensity was found on the endothelial cells of the plexus profundus and on perifollicular blood vessels, while the strongest follicular ICAM-1 IR was detected on piORS keratinocytes. In addition, the ICAM-1 IR patterns in the hair matrix and interfollicular epidermis, as well as those on interfollicular dermal cells and dermal papilla fibroblasts, were the same during spontanous anagen as described and documented above for depilation-induced anagen. This excludes the possibility that the observed changes in ICAM-1 IR merely reflect wound healing-related artifacts.
LFA-1 Expression Is Hair Cycle-dependent and Is Apparently Upregulated on HF-associated Immune Cells
Throughout the depilation-induced hair cycle, LFA-1+ cells were detected in the epidermis, in and around the piORS, and scattered in the interfollicular dermis. The highest cutaneous density of LFA-1+ macrophages was found in the upper dermis around HFs with strongly ICAM-1+ piORS (Fig 2K).
The anti-LFA-1 staining intensity and the number of LFA-1+ cells exhibited substantial hair cycle-dependent fluctuations. Immediately after anagen induction by depilation, the LFA-1 IR, as well as the number of dermal LFA-1+ macrophage-like cells and the number of intraepithelial LFA-1+ Langerhans cells, declined substantially compared to telogen (Day 0). During middle anagen (Day 8 p.d.), a strong increase in LFA-1 IR and a numerical increase of dermal LFA-1+ macrophage-like cells were noted.
During late anagen and the anagencatagen transition (Days 1218 p.d.), LFA-1 IR was seen on macrophage-like cells that accumulated around and inside the piORS (Fig 2K). These intraepithelial LFA-1+ cells in the piORS co-localized with markers for intrafollicular T-cells and Langerhans cells (not shown; cf.
ICAM-1 and LFA-1 mRNA Expression
ICAM-1 and LFA-1 mRNA steady-state levels in full-thickness back skin homogenates of adolescent C57BL/6 mice were assessed by semiquantitative RT-PCR (Fig 5). This revealed a significant decline of ICAM-1 transcript levels early after depilation-induced anagen development (Days 13 p.d.) compared to telogen (p<0.01) and a significant upregulation during middle anagen (Day 8 p.d) (p<0.05). During the subsequent anagencatagentelogen transition, ICAM-1 transcript levels again declined significantly (p<0.01). These hair cycle-associated fluctuations in ICAM-1 transcript levels corresponded well to the hair cycle-related changes noted in ICAM-1 antigen expression (Fig 4; Table 1). Interestingly, almost the same fluctuations of LFA-1 mRNA steady-state levels were found as for ICAM-1. A significant decline of the LFA-1 transcript levels was seen immediately after anagen induction (p<0.01), a significant increase on Day 8 p.d. (p< 0.05), and again a significant decline during the anagen VIcatagentelogen transition (p<0.01) (Fig 5D). Thus, the steady-state levels for both ICAM-1 and LFA-1 mRNA peaked in mouse skin with almost all HFs in anagen VI or catagen.
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ICAM-1-deficient Mice Show Catagen Acceleration
To further probe the concept that ICAM-1 expression is functionally important for HF regression, the first spontaneous postnatal catagen development was compared by quantitative histomorphometry between ICAM-1 knockout mice and age-matched wild-type littermates. Icamtm1Bay knockout mice displayed a statistically significantly accelerated HF regression compared to wild-type controls (Fig 6). At Day 18 post partum, a significantly higher percentage of HFs in wild-type mice were still in early catagen (p<0.02) compared to HFs in ICAM-1 knockout mice, and vice versa, a significantly higher percentage of HFs in ICAM-1 knockout mice were already in late catagen (p<0.05) compared to HFs in wild-type littermates.
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Discussion |
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In this study we demonstrate that mouse skin and HFs exhibit a more widespread and much more dynamic constitutive ICAM-1 expression pattern (Fig 1 Fig 2 Fig 3) than was previously recognized (
Four observations suggest a functionally important role for ICAM-1-related signaling in the control of HF regression. Increasingly strong ICAM-1 expression during skin and HF morphogenesis can be found only when the HFs enter into late neonatal anagen (Fig 1A1C) and their first catagen stage. ICAM-1 expression in adolescent mouse skin peaks during the middle and late stages of synchronized HF regression (catagen), at both the protein (Fig 2B, Fig 2E2G, Fig 2I, Fig 3, and Fig 4; Table 1) and the mRNA level (Fig 5). Finally, ICAM-1-deficient mice display accelerated catagen development compared to wild-type controls (Fig 6). This makes ICAM-1 the first adhesion molecule to be implicated in catagen control. Previously, only secreted cytokines, growth factors and hormones (cf.
Despite identical morphological appearance, neighboring mouse pelage follicles of identical cycle stage differ in their ICAM-1 expression pattern. Furthermore, each hair cycle stage is characterized by a changing percentage of selected, rather regularly distributed follicle populations that display a defined ICAM-1 expression pattern (Fig 1 Fig 2 Fig 3; Table 1). The ICAM-1 expression of cells is widely accepted to be under the control of their local cytokine milieu, with practically all proinflammatory cytokines upregulating ICAM-1 expression (
ICAM-1 expression on endothelial cells (Fig 2J) and piORS keratinocytes (Fig 2B) may primarily serve immunological functions. Vascular ICAM-1 expression is essential for leukocyte recruitment into inflammatory sites (cf. or IFN
). This, in turn, may attract dendritic epidermal T-cells and Langerhans cells to accumulate in this region (
Originally, ICAM-1 was mainly viewed as a simple "glue" for ß2-integrin binding. This view has been changed since the recognition that ICAM-1 also serves intracellular signaling functions. For example, antibody cross-linking of ICAM-1 can induce activation of the transcription factor AP-1 as well as IL-1ß transcription (
The precise cause of accelerated catagen development in ICAM-1 -/- mice remains subject to further investigations. Although ICAM-1 deficiency may modulate the extravasation of blood immune cells into the skin, we found no substantial alteration in the number of MAC-1+, LFA-1+, and MHC-II+ immune cells in key anatomic compartments (especially around the regressing epithelial strand) of ICAM-1 -/- mice compared to wild-type controls (not shown). This suggests that catagen acceleration in ICAM-1 -/- mice might rather be due to a systemic alteration of the skin and hair follicle immune system in these mutants, e.g., ICAM-1 deficiency of perifollicular immune cells or fibroblasts may modulate their cytokine release, leading to a catagen-promoting cytokine milieu.
In summary, this study demonstrates that the transient upregulation of cell adhesion molecule expression, such as ICAM-1 and LFA-1, is not limited to pathological conditions (e.g., during inflammation and infection) and that it may also reflect an as yet underinvestigated involvement of ICAM-1 in physiological tissue remodeling processes such as HF involution. Further studies on the role of ICAM-1-related signaling in catagen control may provide one of the missing links between developmental and immunological aspects of hair growth control.
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Acknowledgments |
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Supported in part by grants from the European Union under the Industrial & Materials Technologies Programme (Brite-Euram III: BE97 - 4301) (to IAM,RP) and Wella AG, Darmstadt (to RP), by a grant from Boehringer Ingelheim Fonds to SMR, and by a grant from the National Cancer Institute (CA 34196) (to JPS).
The support and advice of Dr S. Eichmüller, the excellent technical assistance of R. Pliet and E. Hagen, and the help of T. Purkis with Fig 1 are gratefully acknowledged.
Received for publication April 12, 1999; accepted November 10, 1999.
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Literature Cited |
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![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Argyris TS (1967) Hair growth induced by damage. Adv Biol Skin 9:339-345
Ballantyne CM, We OB, Beaudet AL (1989) Nucleotide sequence of the cDNA for mouse intercellular adhesion molecule-1 (ICAM-1). Nucleic Acids Res 17:1035-1048[Abstract]
Barker JN, Mitra RS, Griffiths CE, Dixit VM, Nickoloff BJ (1991) Keratinocytes as initiators of inflammation. Lancet 337:211-214[Medline]
Bos JD (1997) The Skin Immune System. Boca Raton, FL, CRC Press
Breel M, Mebius R, Kraal G (1987) Dendritic cells of the mouse recognized by two monoclonal antibodies. Eur J Immunol 17:1555-1559[Medline]
Chuong CM (1993) The making of a feather: homeoproteins, retinoids and adhesion molecules. BioEssays 15:513-521[Medline]
Chuong CM, Chen HM, Jiang TX, Chia J (1991) Adhesion molecules in skin development: morphogenesis of feather and hair. Ann NY Acad Sci 642:263-280[Abstract]
Cotsarelis G, Paus R (1998) Hair follicle biology in health and disease. N Engl J Med 341:491-497
Davis SL, Hawkins EP, Mason EO, Jr, Smith CW, Kaplan SL (1996) Host defenses against disseminated candidiasis are impaired in intercellular adhesion molecule 1-deficient mice. J Infect Dis 174:435-439[Medline]
Dong ZM, GutierrezRamos JC, Coxon A, Mayadas TN, Wagner DD (1997) A new class of obesity genes encodes leukocyte adhesion receptors. Proc Natl Acad Sci USA 94:7526-7530
Edelman GM (1988) Topobiology: An Introduction to Molecular Embryology. New York, Basic Books
Edelman GM (1992) Morphoregulation. Dev Dyn 193:2-10[Medline]
Eichmüller S, Stevenson PA, Paus R (1996) A new method for double immunolabelling with primary antibodies from identical species. J Immunol Methods 190:255-265[Medline]
Eichmüller S, van der Veen C, Moll I, Hermes B, Hofmann U, MüllerRöver S, Paus R (1998) Clusters of perifollicular macrophages in normal mouse skin: physiological degeneration of selected hair follicles by programmed organ deletion. J Histochem Cytochem 46:361-370
Goebeler M, Gutwald J, Roth J, Meinardus Hager G, Sorg C (1990) Expression of intercellular adhesion molecule-1 in mouse allergic contact dermatitis. Int Arch Allergy Appl Immunol 93:294-299[Medline]
Goebeler M, Henseleit U, Roth J, Sorg C (1994) Substance P and calcitonin gene-related peptide modulate leukocyte infiltration to mouse skin during allergic contact dermatitis. Arch Dermatol Res 286:341-346[Medline]
Goodman T, LeFrancois L (1989) Intraepithelial lymphocytes: anatomical site, not T cell receptor form, dictates phenotype and function. J Exp Med 170:1569-1581[Abstract]
Handjiski B, Eichmüller S, Hofmann U, Czarnetzki BM, Paus R (1994) Alkaline phosphatase activity and localization during the mouse hair cycle. Br J Dermatol 131:303-310[Medline]
Hirai Y, Nose A, Kobayashi S, Takeichi M (1989) Expression and role of E- and P-cadherin adhesion molecules in embryonic histogenesis. II. Skin morphogenesis. Development 105:271-277[Abstract]
Hofmann U, Tokura Y, Nishijima T, Takigawa M, Paus R (1996) Hair cycle-dependent changes in skin immune functions: anagen associated depression of sensitization for contact hypersensitivity in mice. J Invest Dermatol 106:598-604[Abstract]
Holland J, Owens T (1997) Signalling through intercellular adhesion molecule 1 (ICAM-1) in a B cell lymphoma line. The activation of Lyn tyrosine kinase and the mitogen-activated protein kinase pathway. J Biol Chem 272:9108-9112
Kaplan ED, Holbrook KA (1994) Dynamic expression patterns of tenascin, proteoglycans, and cell adhesion molecules during human hair follicle morphogenesis. Dev Dyn 199:141-155[Medline]
Kaufmann Y, Tseng E, Springer TA (1991) Cloning of the mouse lymphocyte function-associated molecule-1 alpha-subunit and its expression in COS cells. J Immunol 147:369-374
King PD, Sandberg ET, Selvakumar A, Fang P, Beaudet AL, Dupont B (1995) Novel isoforms of mouse intercellular adhesion molecule-1 generated by alternative RNA splicing. J Immunol 154:6080-6093
Koyama Y, Tanaka Y, Saito K, Abe M, Nakatsuka K, Morimoto I, Auron PE, Eto S (1996) Cross-linking of intercellular adhesion molecule 1 (CD54) induces AP-1 activation and IL-1beta transcription. J Immunol 157:5097-5103[Abstract]
Kunkel S, Lukas N, Strieler RH (1996) Cytokines and inflammatory disease. In Sirica AE, ed. Cellular and Molecular Pathogenesis. Philadelphia, LippincottRaven, 23-35
Leenen PJ, de Bruijn MF, Voerman JS, Campbell PA, van Ewijk W (1994) Markers of mouse macrophage development detected by monoclonal antibodies. J Immunol Methods 174:5-19[Medline]
Lenz A, Heine M, Schuler G, Romani N (1993) Human and mouse dermis contain dendritic cells. Isolation by means of a novel method and phenotypical and functional characterization. J Clin Invest 92:2587-2596[Medline]
Lindner G, Botchkarev VA, Botchkarev NV, Ling G, van der Veen C, Paus R (1997) Analysis of apoptosis during mouse hair follicle regression (catagen). Am J Pathol 151:1601-1617[Abstract]
Maurer M, Fische E, Handjiski B, Barandi A, Meingasser J, Paus R (1997a) Activated skin mast cells are involved in hair follicle regression (catagen). Lab Invest 77:319-332[Medline]
Maurer M, Handjiski B, Paus R (1997b) Hair growth modulation by topical immunophilin ligands: induction of anagen, inhibition of massive catagen development, and relative protection from chemotherapy-induced alopecia. Am J Pathol 150:1433-1441[Abstract]
MüllerRöver S, Paus R (1998) Topobiology of the hair follicle: adhesion molecules as morphoregulatory signals during hair follicle morphogenesis. In Chuong CM, ed. Molecular Basis of Epithelial Appendage Morphogenesis. Austin, TX, Landes Bioscience, 283-314
Nickoloff BJ, Griffiths CE (1991) Aberrant intercellular adhesion molecule-1 (ICAM-1) expression by hair-follicle epithelial cells and endothelial leukocyte adhesion molecule-1 (ELAM-1) by vascular cells are important adhesion-molecule alterations in alopecia areata. J Invest Dermatol 96:91S-92S[Medline]
Parakkal PF (1969) Role of macrophages in collagen resorption during hair growth cycle. J Ultrastruct Res 29:210-217[Medline]
Paus R (1996) Control of the hair cycle and hair diseases as cycling disorders. Curr Opin Dermatol 3:248-258
Paus R (1997) Immunology of the hair follicle. In Bos JD, ed. The Skin Immune System. Boca Raton, FL, CRC Press
Paus R, Böttge J-A, Henz B, Maurer M (1996) Hair growth modulation by immunosuppression. Arch Dermatol Res 288:408-410[Medline]
Paus R, Cotsarelis G (1999) The biology of hair follicles. N Engl J Med 341:491-497
Paus R, Czarnetzki BM (1992) New perspectives in hair research: in search of the "biological clock" of the hair cycle. Hautarzt 43:264-271[Medline]
Paus R, Eichmüller S, Hofmann U, Czarnetzki BM (1994a) Expression of classical and non-classical MHC class I antigens in mouse hair follicles. Br J Dermatol 131:177-183[Medline]
Paus R, Foitzik K, Welker P, BulfonePaus S, Eichmüller S (1997) Transforming growth factor-ß receptor type I and type II expression during mouse hair follicle development and cycling. J Invest Dermatol 109:518-526[Abstract]
Paus R, Handjiski B, Czarnetzki BM, Eichmüller S (1994b) A mouse model for inducing and manipulating hair follicle regression (catagen): effects of dexamethasone and cyclosporin A. J Invest Dermatol 103:143-147[Abstract]
Paus R, Hofmann U, Eichmüller S, Czarnetzki BM (1994c) Distribution and changing density of gamma-delta T cells in mouse skin during the induced hair cycle. Br J Dermatol 130:281-289[Medline]
Paus R, Maurer M, Slominski A, Czarnetzki BM (1994d) Mast cell involvement in mouse hair growth. Dev Biol 163:230-240[Medline]
Paus R, Stenn KS, Link RE (1990) Telogen skin contains an inhibitor of hair growth. Br J Dermatol 122:777-784[Medline]
Paus R, van der Veen C, Eichmüller S, Kopp T, Hagen E, MüllerRöver S, Hofmann U (1998) Generation and cycling remodeling of the hair follicle immune system in mice. J Invest Dermatol 111:7-18[Abstract]
PethöSchramm A, Müller HJ, Paus R (1996) FGF5 and the mouse hair cycle. Arch Dermatol Res 288:264-266[Medline]
Philpott MP, Paus R (1998) Principles of hair follicle morphogenesis. In Chuong CM, ed. Molecular Basis of Epithelial Appendage Morphogenesis. Austin, TX, Landes Bioscience, 75-103
Rückert R, Hofmann U, van der Veen C, BulfonePaus S, Paus R (1998) MHC class I expression in mouse skin: developmentally controlled and strikingly restricted intraepithelial expression during hair follicle morphogenesis and cycling, and response to cytokine treatment in vivo. J Invest Dermatol 111:25-30[Abstract]
Sambrook J, Fritsch EF, Maniatis T (1989) Molecular Cloning. 2nd ed Cold Spring Harbor, NY, Cold Spring Harbor Laboratory Press
Scheynius A, Camp RL, Pure E (1993) Reduced contact sensitivity reactions in mice treated with monoclonal antibodies to leukocyte function-associated molecule-1 and intercellular adhesion molecule-1. J Immunol 150:655-663
Schilli MB, Ray S, Paus R, ObiTabot E, Holick MF (1997) Control of hair growth with parathyroid hormone (7-34). J Invest Dermatol 108:928-932[Abstract]
Sligh JE, Jr, Ballantyne CM, Rich SS, Hawkins HK, Smith CW, Bradley A, Beaudet AL (1993) Inflammatory and immune responses are impaired in mice deficient in intercellular adhesion molecule 1. Proc Natl Acad Sci USA 90:8529-8533
Springer T, Davignon D, Ho M, Kurzinger K, Martz E, SanchezMadrid F (1982) LFA-1 and Lyt-2,3 molecules associated with T lymphocyte-mediated killing; and Mac-1, an LFA-1 homologue associated with complement receptor function. Immunol Rev 68:171-195[Medline]
Springer T, Galfré G, Secher D, Milstein C (1979) Mac-1: a macrophage differentiation antigen identified by monoclonal antibody. Eur J Immunol 9:301-306[Medline]
Springer TA (1990) Adhesion receptors of the immune system. Nature 346:425-434[Medline]
Springer TA (1994) Traffic signals for lymphocyte recirculation and leukocyte emigration: the multistep paradigm. Cell 76:301-314[Medline]
Stenn K, Parimoo S, Prouty S (1998) Growth of the hair follicle: a cycling and regenerating biological system. In Chuong CM, ed. Molecular Basis of Epithelial Appendage Morphogenesis. Austin, Texas, Landes Bioscience Publ, 111-124
Stenn KS, Combates NJ, Eilertsen KJ, Gordon JS, Pardinas JR, Parimo S, Prouty SM (1996) Hair follicle growth controls. Dermatol Clin 14:543-558[Medline]
Straile W, Chase H, Arsenault C (1961) Growth and differentiation of hair follicles between periods of activity and quiescence. J Exp Zool 148:205-221
Tokura Y, Hofmann U, MüllerRöver S, Paus R, Wakita H, Yagi H, Seo N, Furukawa F, Takigawa M (1997) Spontaneous hair follicle cycling may influence the development of mouse contact photosensitivity by modulating keratinocyte cytokine production. Cell Immunol 178:172-179[Medline]
van de Stolpe A, van der Saag PT (1996) Intercellular adhesion molecules-1. J Mol Med 74:13-33[Medline]
van Kooyk Y, Figdor CG (1997) Signalling and adhesive properties of the integrin leucocyte function-associated antigen (LFA-1). Biochem Soc Trans 25:515-520[Medline]
Van Vliet E, Melis M, Foidart JM, Van Ewijk W (1986) Reticular fibroblasts in peripheral lymphoid organs identified by a monoclonal antibody. J Histochem Cytochem 34:883-890[Abstract]
Van Vliet E, Melis M, Van Ewik W (1984) Monoclonal antibodies to stromal cell types of the mouse thymus. Eur J Immunol 14:524-529[Medline]
Vielkind U, Sebzda MK, Gibson IR, Hardy MH (1995) Dynamics of Merkel cell patterns in developing hair follicles in the dorsal skin of mice, demonstrated by a monoclonal antibody to mouse keratin 8. Acta Anat 152:93-109[Medline]
Westgate GE, Craggs RI, Gibson WT (1991) Changes in the histology and distribution of immune cell types during the hair growth cycle in hairless rat skin. Ann NY Acad Sci 642:493-495[Medline]
Williams IR, Kupper TS (1994) Epidermal expression of intercellular adhesion molecule 1 is not a primary inducer of cutaneous inflammation in transgenic mice. Proc Natl Acad Sci USA 91:9710-9714
Xu H, Gonzalo JA, St Pierre Y, Williams IR, Kupper TS, Cotran RS, Springer TA, Gutierrez Ramos JC (1994) Leukocytosis and resistance to septic shock in intercellular adhesion molecule 1-deficient mice. J Exp Med 180:95-109[Abstract]