Interleukin 6 Function in the Skin and Isolated Keratinocytes Is Modulated by Hyperglycemia

Abstract

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.

The Immune Functions of Keratinocytes in Skin Wound Healing

“…As the primary cell type in the epidermis, keratinocytes produce large amounts of cytokines to initiate and regulate inflammation, including IL-1, -6, -7, -8, -10, -12, -15, -18, and -20, and TNF-α [ 158 ]. Although elevated IL-8 [ 159 ], IL-1 α [ 160 ], TNF-α [ 161 ], IL6 [ 19 , 162 ], and CCL2 [ 163 ] levels have been observed in human chronic wounds, these cytokines are not specifically produced by keratinocytes. Indeed, few studies have provided clear evidence of the contribution of keratinocytes-derived cytokines to wound healing or chronic wound pathology.…”

Royal jelly alleviates the detrimental effects of aging on immune functions by enhancing the in vitro cellular proliferation, cytokines, and nitric oxide release in aged human PBMCS

“…Studies carried out in genetically modified animal models imply that IL‐6 has a profound role in both innate and adaptive immunity to protect the host from a variety of infections, mainly against the bacterial and fungal pathogens (Rose‐John et al., 2017). IL‐6 is an important cytokine implicated in wound healing (Lee et al., 2019), and according to Gerstein et al. (1993), many scientific reports have proved age‐related differences in wound healing.…”

“…Studies carried out in genetically modified animal models imply that IL-6 has a profound role in both innate and adaptive immunity to protect the host from a variety of infections, mainly against the bacterial and fungal pathogens (Rose-John et al, 2017). IL-6 is an important cytokine implicated in wound healing (Lee et al, 2019), and according to Gerstein et al (1993) wounds with the inflammation, we suppose that the altered levels of IL-6 observed during aging in our study may be partially responsible for the delayed wound healing commonly observed in the elderly. Several previous studies have shown a rise in blood circulatory IL-6 during aging (Forsey et al, 2003;Stowe et al, 2009), however, Nevalainen et al (2015) demonstrate a low baseline expression level of the IL-6 transcript in aged PBMCs.…”

The impact of different suturing techniques for abdominal fascia closure on the Interleukin-6 expressions in Rattus norvegicus

“…Experimental research conducted by Lin et al [ 10 ] explains that in rats with IL-6 deficiency there is a decrease in the number of angiogenic and fibrogenic growth factors so that angiogenesis and collagen deposition are delayed. The study by Lee et al [ 14 ] explains IL-6-deficient mice showed an early phase delay in wound healing, as well as in hyperglycemic mice. IL-6 was significantly higher (sixfold) in hyperglycemic animals at days 1, 7, and 10 [ 14 ].…”

“…The study by Lee et al [ 14 ] explains IL-6-deficient mice showed an early phase delay in wound healing, as well as in hyperglycemic mice. IL-6 was significantly higher (sixfold) in hyperglycemic animals at days 1, 7, and 10 [ 14 ]. Our study shows an almost significant change in IL-6 expression in the small stitch group between days 4 and 7.…”