Interleukin 10 but not interleukin 4 is a natural suppressant of cutaneous inflammatory responses.

Abstract

SummaryWe have examined the role of endogenously produced interleukin (IL) 4 and IL-10 in the regulation of inflammatory and immune reactions in the skin. In these experiments, irritant and contact hypersensitivity (CH) responses were elicited in mice with targeted disruptions of the IL-4 (IL-4T) or IL-10 (IL-10T) gene. Our study showed that IL-4T and wild-type (wt) mice exhibited equivalent responses to the irritant croton oil. In contrast, the response of IL-10T mice challenged with croton oil was abnormally increased. When IL-10T mice were exposed to a higher dose of irritant, irreversible tissue damage occurred. By comparison, any treatment of wt mice with croton oil resulted in far less tissue damage and resolution of inflammation. Neutralizing antibody studies demonstrated that the necrosis ,hat occurred in Ibl0T mice was due to the overproduction of tumor necrosis factor. The anti-tumor necrosis factor antibody treatment of IL-10T mice did not significantly reduce the edema or the influx of inflammatory cells, suggesting that these changes were due to the uncontrolled production of other proinflammatory cytokines. T cell-dependent immune responses were also evaluated using the contact sensitizer oxazolone. The response of IL-4T mice did not differ from wt mice. In contrast, ILol0T mice mounted an exaggerated CH response, increased in both magnitude and duration as compared with wt mice. Based on these studies, we have concluded that II,-10, but not IL-4, is a natural suppressant of irritant responses and of CH, and it limits immunopathologic damage in the skin.

Regulation of cytokine production during phagocytosis of apoptotic cells

“…These initial studies were soon followed by extensive research showing that IL-10 is an inhibitor of a broad spectrum of monocyte/macrophage functions, including cytokine synthesis, nitric oxide production, and expression of MHC class II and costimulatory molecules such as CD80/CD86 [67][68][69][70][71][72][73][74]. Investigations in numerous inflammatory disease models including chronic enterocolitis, cutaneous inflammatory condition, endotoxic shock and Shwartzman reaction, and autoimmune encephalomyelitis in IL-10-deficient mice have yielded strong evidence that IL-10 plays a central role in vivo in restricting inflammatory responses [75][76][77][78][79]. However, endogenous IL-10 production and systemic administration can also exacerbate macrophage-and T-cell dysfunction, decrease T-cell apoptosis, blunt antimicrobial activity, and increase mortality in other less acute bacterial models of sepsis or after thermal injury [80].…”

Role of interleukin‐4 and interleukin‐10 in murine collagen‐induced arthritis. Protective effect of interleukin‐4 and interleukin‐10 treatment on cartilage destruction

“…IL-10 knockout mice showed normal immune responses and hematopoietic development at an early age, but older animals had chronic enterocolitis (52). Endotoxic shock and cutaneous inflammatory responses were enhanced in IL-10 knockouts (53,54). Likewise, blocking of endogenous IL-10 with neutralizing antibodies enhanced endotoxic shock, IgG immune complex-induced lung injury, and the severity of CIA (27,28,30).…”

Interleukin‐10 derived from macrophages and/or neutrophils regulates the inflammatory response to LPS but not the response to CpG DNA

“…Likewise, the response of the skin to tetradecanoylphorbol-acetate (TPA) containing irritants, which is a function of cutaneous innate immunity, is clearly enhanced in IL-10-deficient mice in comparison to WT mice [12]. Thus, innate responses as well as Th1 responses are subject to regulation by IL-10.…”