Diabetes currently affects over twenty-five million Americans. Annual health care cost of diabetes exceeds $254 billion and is associated with a distinct set of diabetic complications that include delayed wound healing and diabetic ulcers. Interleukin 6 (IL-6) plays an important role in wound healing and is known to be elevated in the serum of both type I and type II diabetes patients. This study assesses the expression and function of IL-6 in the hyperglycemic epidermis and keratinocyte culture. Streptozotocin-treated mice were wounded six weeks after induction of hyperglycemia. Wound closure, protein, and mRNA expression were assessed up to 13 days of postwounding. Wound closure was delayed 4-5 days in hyperglycemic animals. Hyperglycemic wounds displayed greater IL-6 and IL-6Rα protein expression at 1, 7, and 10 days of postwounding compared to euglycemic control. However, IL-6Rα mRNA expression was reduced at all time points beyond day 1, while IL-6 mRNA expression did not significantly differ at any time point. SOCS3 mRNA expression was higher in the hyperglycemic skin at every time point. Imaging of fluorescent immunohistology also revealed significantly lower expression of SOCS3, but higher nuclear pSTAT3 in the epidermis of the hyperglycemic skin. Primary mouse keratinocytes cultured in high glucose for 7 days displayed 2-fold higher IL-6Rα mRNA and higher rmIL-6-induced nuclear pSTAT3, but lower SOCS3 basal levels compared to normal glucose-cultured cells. Thus, it appears that delayed diabetic skin wound healing is associated with increased induction and expression of IL-6 and its receptor, but its function in epidermal keratinocytes may be impaired.

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Irritant contact dermatitis (ICD) is an acute inflammatory response that is ranked the 2nd most prevalent occupational injury associated with workman’s compensation. Interleukin-6 (IL-6), a pro-inflammatory cytokine produced in the skin, is closely associated with healing and decreased levels are associated with more severe ICD. The phenotypic nature of the macrophage infiltrate during skin inflammation can greatly influence damage and healing during ICD. The pro-inflammatory, classically activated (M1) macrophage produce cytokines such as IL-6, IL-1, and TNFα, while alternatively activated (M2) macrophages produce IL-10 and TGFβ, and are thought to be associated with tissue repair. IL-6 may play a regulatory role in mediating the M1 versus M2 phenotypic change in skin. To examine the role of IL-6 in ICD, IL-6KO and C57 mice were exposed to benzoalkonium chloride (BKC) for 7 days. IL-6KO mice displayed decreased expression of CD206 (M2) as compared to CD86 (M1) and the ration of CD86:CD206 was significantly increased in IL-6KO mice compared to control. Multiplex protein analysis showed expression of multiple M1-related cytokines such IFN-g, CCL3, CCL4, CCL5, and CCL7 significantly modulated in IL6-KO BKC treated mice compared to C57. Additionally, M2 related cytokine/chemokine receptors IL-4R and CCR1 were significantly dysregulated in IL-6KO BKC treated mice. IL-6 treatment of RAW cells enhanced the expression of CD206 in manner similar to IL-4. Overall, these results further confirm a role for IL-6 in macrophage polarization and could eventually result in the development of therapies for dermatitis based on this cytokines activity.

Petroleum crude oil spills are common and vary in size and scope. Spill response workers throughout the course of remediation are exposed to so-called weathered oil and are known to report diverse health effects, including contact dermatitis. A murine model of repeated exposure to weathered marine crude oil was employed utilizing two strains of mice, C57BL/6 and BALB/c, to investigate the pathology of this irritant and identify the principal hydrocarbon components deposited in skin. Histopathology demonstrated clear signs of irritation in oil-exposed skin from both mouse strains, characterized by prominent epidermal hyperplasia (acanthosis). BALB/c mice exposed to oil demonstrated more pronounced irritation compared with C57BL/6 mice, which was characterized by increased acanthosis as well as increased inflammatory cytokine/chemokine protein expression of IL-1β, IL-6, CXCL10, CCL2, CCL3, CCL4, and CCL11. A gas chromatography/mass spectrometry method was developed for the identification and quantification of 42 aliphatic and EPA priority aromatic hydrocarbons from full thickness skin samples of C57BL/6 and BALB/c mice exposed to oil samples. Aromatic hydrocarbons were not detected in skin; however, aliphatic hydrocarbons in skin tended to accumulate with carbon numbers greater than C16. These preliminary data and observations suggest that weathered crude oil is a skin irritant and this may be related to specific hydrocarbon components, although immune phenotype appears to impact skin response as well.