Department of Cellular Biology and Anatomy, Louisiana State University Health Sciences Center, Shreveport, Louisiana 71130
1 To whom correspondence should be addressed at Dept. Cellular Biology & Anatomy, LSU Health Sciences Center, 1501 Kings Hwy., Shreveport, LA 71130. Fax: (318) 675-5889. E-mail: spruet{at}LSUHSC.edu.
Received April 28, 2005; accepted May 27, 2005
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ABSTRACT |
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Key Words: sodium methyldithiocarbamate; immune system; toll-like receptor 4; methylisothiocyanate; Escherichia coli.
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INTRODUCTION |
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In previous studies, we demonstrated that SMD suppresses several immune system parameters in mice (Keil et al., 1996; Myers et al., 2005; Padgett et al., 1992
; Pruett et al., 1992
), but its effects on the production of cytokines by macrophages have not been investigated. The exacerbation of asthma caused by SMD (Cone et al., 1994
) suggests the possibility that it may shift the predominance of T helper cells (Th) from Th1 to Th2. The predominance of Th1 vs. Th2 cells and their corresponding cytokines is determined in part by the predominance of cytokines that support activation of Th1 cells (e.g., IL-12 or IFN-
) compared to cytokines that favor the predominance of Th2 cells (e.g., IL-10). These cytokines are produced primarily by antigen presenting cells such as macrophages and dendritic cells (Dalod et al., 2002
; Trinchieri, 1993
; Yi et al., 2002
). Pro-inflammatory cytokines produced by macrophages are also critically important in innate resistance to infection (Weighardt et al., 2000
). In particular, peritoneal macrophages are critical in resistance to peritonitis (Dunn et al., 1987
; Matsukawa et al., 1999
; Vuopio-Varkila, 1988
), and the macrophage-derived cytokines IL-12 and IL-10 are also involved (Sewnath et al., 2001
; Takano et al., 1998
; Zisman et al., 1997
).
Following our initial observation in this study that SMD alters LPS-induced cytokine production by peritoneal macrophages, we developed the working hypothesis that this might be mediated by inhibition of cellular signaling and that it might lead to suppression of innate immunity. The present study was conducted to evaluate this working hypothesis. The major signaling mechanisms activated by LPS through TLR4 are NF-B and MAP kinases, which activate several transcription factors, of which AP-1 is representative. AP-1 is also important in the expression of the cytokines investigated here. Therefore, NF-
B, MAP kinases, and AP-1 were investigated. Early events in TLR4 signaling include binding of an adapter molecule (generally MyD88) to the receptor (Kawai et al., 1999
) followed by activation of interleukin 1 receptor associated kinases (IRAK) 1 and 4 (Li et al., 2002
). Thus, the effects of SMD on IRAK-1 and MyD88 were examined to determine if it acts early in the signaling pathway. To evaluate innate immunity, a model in which the cell type under investigation here (peritoneal macrophages) is known to be important was selected. Thus, resistance to peritonitis caused by injection of large numbers of non-pathogenic Escherichia coli was measured.
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MATERIALS AND METHODS |
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Mice were treated with bacterial lipopolysaccharide (LPS, from Escherichia coli 0128:B12 from Sigma Chemical Co. or ultrapure LPS from Salmonella minnesota from List Labs) by iv injection in a lateral tail vein. Standard LPS is referred to as LPS, and ultrapure LPS is referred to as pure or ultrapure LPS in subsequent sections. The dosage was 60 µg/mouse, a dosage we have previously shown to induce cytokines but not to be lethal (Pruett et al., 2004b). Sodium methyldithiocarbamate (SMD) was obtained from Chem Service, Inc. and methylisothiocyanate (MITC) was obtained from Sigma Chemical. They were dissolved in tissue culture grade water. Dissolving MITC required heating to 56°C. After it was dissolved, the solution was separated into aliquots and stored frozen until use. SMD was prepared fresh for each experiment. Both solutions were filter sterilized before use. Mice were treated with SMD or MITC by oral gavage. In one experiment mice were treated with the TLR3 agonist polyinosinic polycytidylic acid (poly I:C) at 100 µg/mouse, intravenously as in our previous studies (Pruett et al., 2004a
).
For host resistance studies, mice were challenged by ip injection of log phase non-pathogenic Escherichia coli (E. coli), as described previously (Pruett et al., 2004b). The E. coli strain used was isolated from one of the mice in our colony, and its identity was confirmed using the Marieux Vitek gram negative identification system. The dosages of E. coli required to cause lethal peritonitis were found to be comparable to those reported by other investigators (Takano et al., 1998
; Zhao et al., 2001
). After challenge, the mice were observed at least every 6 h and animals that were moribund were euthanized and counted as non-survivors. However, in the experiments shown most animals died between observations and most non-survivors shown in the graphs represent animals that died rather than animals that were euthanized.
Peritoneal fluid and cells were obtained by peritoneal lavage using phosphate buffered saline with 10% fetal bovine serum. First, a lavage was performed using 1 ml of fluid with typical recoveries of 0.60.7 ml. After centrifugation, the supernatant fluid was used to quantify cytokines without the dilution effect that would result from a larger volume of lavage fluid. To assure complete recovery of peritoneal cells, a second lavage was performed using 7 ml of lavage fluid. After centrifugation, the cells from both lavages were pooled. Cell counts (by Coulter counter) and differential counts in this and previous studies (Pruett et al., 2004a,b
), demonstrate that typical yields of cells are 23 x 106/mouse, and typical differential counts are 8095% macrophages, 415% lymphocytes, 15% neutrophils, and occasional basophils and eosinophils.
Serum corticosterone analysis.
Serum from mice treated dermally with SMD was analyzed for corticosterone to determine if dermal application induces a neuroendocrine stress response, as does po administration (Myers et al., 2005). Mice were bled by decapitation within 3 min from the time the cage was obtained from the animal room to prevent handling-induced stress. Corticosterone was analyzed using a radioimmunoassay kit from DPC (Los Angeles, CA), as in our previous studies (Pruett et al., 1999, 2000
, 2003c
).
Cytokine and chemokine analysis.
Samples were analyzed for quantities of IL-10, IL-12 (p40), and CXCL9 using matched ELISA reagents from BD Pharmingen. In one experiment IL-12 (p70) and IL-10 were analyzed using a BioPlex multiplexed bead array kit from BioRad. For analysis of intracellular cytokines, peritoneal cells from each mouse were resuspended in 120 µl of PBS containing 0.5% Tween 20 and sonicated for 15 s using a needle-type probe. After centrifugation at 15,000 x g for 10 min, the supernatant fluid was removed and analyzed for cytokines.
Western blot and Bioplex analysis of signaling.
For signaling studies peritoneal cells were isolated quickly using ice cold buffer, and cells were kept on ice for no more than 30 min before centrifugation (at 4°C). Whole cell extracts or nuclear extracts were prepared from peritoneal cell pellets just as described in our previous studies (Pruett et al., 2003b, 2004a
). In a previous study, we determined that signaling parameters were not significantly affected following even longer periods of time than this, if they were kept cold (Pruett et al., 2003b
). Protein in each sample was quantified using the BCA method (Pierce Chemical) with bovine serum albumin as a standard. An equivalent amount of protein from each mouse (10 µg for NF-
B and 20 µg for others) was mixed with sample buffer, subjected to SDS-PAGE, blotted onto a PVDF membrane, labeled with primary and secondary antibodies (anti-NF-
B, p65, #C-20; anti-IRAK-1, #H-273; peroxidase coupled anti rabbit polyclonal IgG secondary antibody, #SC-7883; Santa Cruz Biotechnology), and bands were developed using the ECL chemiluminescence system (Amersham). The membrane was then used to expose photographic film. Proteins were quantitated using NIH Image software and the included macro for gel analysis.
RNAse Protection Assay.
Expression of cytokine mRNA was analyzed using a probe set from BD Pharmingen (RiboQuant mCK2b). RNA was isolated from all cells obtained from each mouse using Tri Reagent and quantified by the ratio of absorbance at 280 and 260 nm. RNAse protection assay was done just as described in our previous studies (Pruett et al., 2003a, 2004a
; Zheng and Pruett, 2000
), and X-ray films of gel autoradiographs were quantified using NIH Image software with the included macro for analysis of bands on gels. A long exposure film was used to increase sensitivity for quantitation of mRNA expressed at low levels and a short exposure film was used to prevent saturation of mRNA bands expressed at high levels as well as housekeeping mRNAs L32 and GAPDH.
Statistical analysis.
Data were analyzed by analysis of variance followed by the Student Newman Keul's (SNK) post hoc test to compare each mean to every other mean. Comparisons in which p < 0.05 were regarded to be significantly different. In most figures, values significantly different from the LPS or poly I:C only group are indicated by asterisks. Survival analysis was done with the Log-rank test. All analyses were done using Prism 4.0 software (GraphPad Software, San Diego, CA).
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RESULTS |
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The Effect of SMD on LPS-Induced IRAK-1 Degradation and the Role of MyD88
The results shown in Figure 3 indicate that LPS induces the degradation of IRAK-1 in peritoneal cells and that SMD does not affect this degradation. Phosphorylation of IRAK-1 is one of the early events in TLR4 signaling, and hyperphosphorylation leads to ubiquitination and degradation (Yamin and Miller, 1997). Thus, the absence of change in IRAK-1 degradation suggests that SMD does not act early in the TLR signaling pathway. The major adaptor molecule in TLR4 signaling is apparently MyD88, but other adapters can also bind to TLR4 and mediate signaling. The results shown in Figure 3 demonstrate that cytokine production is considerably reduced in MyD88 knockout mice, but the key effects of SMD still occur (decreased IL-12 and increased IL-10) in MyD88 knockout mice. Again, this suggests that the action of SMD is downstream of the early events of signaling and is not specific for MyD88. This is also suggested by the observation that SMD suppresses IL-12 and CXCL9 production and enhances IL-10 production induced by polyinosinic polycytidylic acid (poly I:C), which acts through TLR3 and does not utilize MyD88 (see supplemental data online).
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DISCUSSION |
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The molecular mechanism by which SMD acts to inhibit signaling is not revealed by these results, but the chemical properties and physiological effects of SMD suggest some possibilities. SMD has a free S group that allows it to function as a reducing agent and free radical scavenger (Motohashi and Mori, 1986; Zanocco et al., 1989
). SMD spontaneously degrades in vitro and in vivo to form methylisothiocyanate (MITC), and MITC reacts with reduced glutathione (GSH) and causes it to be transported from cells (Thompson et al., 2002
). SMD is an excellent chelator of cupric ions (Gray, 1964
), and dithiocarbamates may either deplete copper from the animal or increase transport of copper into cells (Nobel et al., 1995
; Shimada et al., 2005
). Both cellular redox status and copper availability can have profound effects on cellular signaling (including MAP kinases and AP-1) (Chen et al., 2000
; Chung et al., 2000
). Additionally, we have reported that SMD induces a substantial neuroendocrine stress response leading to elevated levels of corticosterone sufficient to cause thymic hypoplasia (Myers et al., 2005), and increased corticosterone was also observed following dermal dosing in the present study. Any of these mechanisms could explain the effects of SMD, and experiments are in progress to evaluate them.
The observation that MITC causes similar effects as SMD on IL-10 and IL-12 expression suggests the possibility that MITC resulting from breakdown of SMD is mostly responsible for the effects of the SMD. Further studies should demonstrate if there are effects mediated by SMD that are not caused by MITC.
The effects of SMD on TLR signaling contrast with the effects of ethanol. Ethanol acts further upstream and significantly inhibits the degradation of IRAK-1. It also inhibits activation of NF-B as well as MAP kinases and AP-1 (Pruett et al., 2004a
). It is interesting in this regard that ethanol also increases IL-10 expression and decreases IL-12 expression (Pruett et al., 2003a
). This suggests that these effects depend more on suppression of AP-1 activation than on suppression of NF-
B activation (which does not occur in SMD treated mice). In addition, the observation that ethanol and SMD have different effects on signaling indicates that the action of SMD on signaling is not primarily mediated by the stress response it induces. Ethanol produces a similar stress response (Pruett et al., 2003c
) as SMD (Myers et al., in press
), and if stress mediators (such as corticosterone) were responsible for the alterations in TLR4 signaling, it would be expected that similar changes in signaling would be caused by ethanol and SMD.
The results presented here do not conclusively establish that the altered cytokine responses caused by SMD are responsible for the decreased resistance to E. coli. It has been established that many of the genes regulated by E. coli treatment of mice are similarly regulated by LPS (Huang et al., 2001; Nau et al., 2003
). Considering that increased IL-10 has been reported to decrease E. coli clearance (Takano et al., 1998
) and that some of the cytokines suppressed by SMD are involved in resistance to E. coli or similar bacteria (Cross et al., 1995
; Kinoshita et al., 2004
; Zisman et al., 1997
), it seems likely that these changes do contribute to decreased resistance. The mouse model used here is relevant to a variety of conditions in humans (e.g., abdominal trauma, appendicitis, diverticulitis, chronic alcoholism) in which large numbers of normally non-pathogenic bacteria enter the peritoneal cavity from the gastrointestinal tract (Pruett et al., 2004b
). It remains to be determined whether death is caused by overgrowth of bacteria leading to intravascular coagulation and multiple organ failure or whether there is a rebound in the production of pro-inflammatory cytokines leading to systemic inflammatory response syndrome, shock, and death. A rebound effect leading to increased concentrations of MIF, for example, after the effects of SMD subside, would be expected to increase lethality due to systemic inflammatory response syndrome (Roger et al., 2001
).
The results presented here are relevant with regard to environmental and occupational exposure of persons to SMD and MITC. The dosages of SMD used here could occur as a result of occupational exposure to commercial SMD preparations (Padgett et al., 1992). In addition the reported dosage of MITC for a child near fields treated with SMD is up to 1.02.5 mg/kg/day (Thongsinthusak, 2000
). Expressing this dosage range on the basis of body surface area instead of body weight in humans and mice indicates that this dosage range in humans encompasses a dosage of 17 mg/kg in mice (calculated as described in our previous study) (Padgett et al., 1992
). This dosage was sufficient to significantly decrease serum IL-12 expression in the present study. Exacerbation of asthma has been reported following exposure to SMD or MITC, and this would be consistent with increased IL-10 and decreased IL-12 leading to a shift toward a Th2 response.
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SUPPLEMENTARY DATA |
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ACKNOWLEDGMENTS |
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