The Role of IL-6 Receptor in Irritant Dermatitis

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DESCRIPTION (provided by applicant): Of reported occupational injury associated with workman's compensation, contact dermatitis ranks second most prevalent over all. Chemical irritant contact dermatitis (ICD) is characterized by an acute inflammatory response that is modulated by cytokines. However, it is not known if specific cytokines are associated with irritant type or strength. This knowledge may be of significant predictive value when judging the irritancy potential of a chemical, or an individual's response to irritant exposure. The proinflammatory cytokine interleukin 6 (IL-6) is closely associated with skin healing and barrier maintenance. Preliminary data indicate that mice deficient in IL-6 display more severe ICD than WT or IL-6 overexpressing mice. Thus, the hypothesis is proposed that modulation of skin IL-6 function contributes to severity of dermatitis. Three specific aims are proposed. The first specific aim will investigate whether the protective effects of IL-6 could manifest themselves through altered barrier and/or inflammatory gene expression. To examine both possibilities, differential gene expression in skin of WT, IL-6KO and Tg (IL6) mice during ICD induced by several common irritants will be assessed. ICD lesions from mice will be examined utilizing PCR arrays focusing on inflammatory and structural genes. Protein expression will be confirmed via immunohistology, multiplex ELISA and/or Western blot. The second specific aim will investigate [the protective mechanism of IL-6 through evaluation of soluble protein administration]. [Exogenous proteins indicated by aim one, or rmIL-6 will be evaluated by] intradermal injection of the protein solution into skin of WT or IL-6KO mice. [Alternately, if a protein cannot be acquired, the gene will be delivered to skin via a viral vector]. Once treated, mice are exposed to chemical irritants and the extent of inflammation will be determined by visualization and histopathology. The third specific aim will investigate whether known polymorphisms (SNPs) of genes associated with IL- 6 contribute to ICD susceptibility in humans through the modulation of expression of this cytokine, or the function of its receptor. Samples from patch-tested patients will be screened for 55 IL-6 associated gene SNPs. Polymorphisms will be determined by QPCR, and statistical analysis will be performed to show correlations to pathology. [To further investigate the mechanisms of SNPs, transgenic mice that express human gene SNPs that are strongly associated with ICD severity, will be generated to directly model the human pathology. ICD will be assessed as described in specific aim one.] If the hypothesis of this proposal is correct, IL-6 would prove to be a useful marker in determining irritancy potential of a chemical, and whether certain populations may be more prone to developing ICD. This research may also provide the rational for IL-6 based therapies that may find use in the prophylaxis or treatment of occupational dermatitis.