Combined deletion of p38γ and p38δ reduces skin inflammation and protects from carcinogenesis

Abstract

The contribution of chronic skin inflammation to the development of squamous cell carcinoma (SCC) is poorly understood. While the mitogen-activated protein kinase p38α regulates inflammatory responses and tumour development, little is known about the role of p38γ and p38δ in these processes. Here we show that combined p38γ and p38δ (p38γ/δ) deletion blocked skin tumour development in a chemically induced carcinogenesis model. p38γ/δ deletion reduced TPA-induced epidermal hyperproliferation and inflammation; it inhibited expression of proinflammatory cytokines and chemokines in keratinocytes in vitro and in whole skin in vivo, resulting in decreased neutrophil recruitment to skin. Our data indicate that p38γ/δ in keratinocytes promote carcinogenesis by enabling formation of a proinflammatory microenvironment that fosters epidermal hyperproliferation and tumourigenesis. These findings provide genetic evidence that p38γ and p38δ have essential roles in skin tumour development, and suggest that targeting inflammation through p38γ/δ offers a therapeutic strategy for SCC treatment and prevention.

Myeloid cell deficiency of p38γ/p38δ protects against candidiasis and regulates antifungal immunity

“…We observed that the lack of p38γ/p38δ caused a remarkable protection to infection (Fig A). To determine whether the effect in survival was due to p38γ/p38δ in myeloid cells, we also analysed mice with myeloid cell‐specific p38γ/p38δ deletion (LysM‐p38γ/δ −/− ; Zur et al , ). In agreement with the observation in p38γ/δ −/− mice, the survival of LysM‐p38γ/δ −/− mice was significantly increased compared with control mice after C. albicans infection (Fig A).…”

Heat Shock Factor 1 Is a Substrate for p38 Mitogen-Activated Protein Kinases

“…7A) (28). In comparison to the parental cells or cells deficient in p38δ, the heat shock-mediated phosphorylation of HSF1 at S326 was reduced by 60% in cells lacking p38γ (Fig.…”

MicroRNA‐351‐5p aggravates intestinal ischaemia/reperfusion injury through the targeting of MAPK13 and Sirtuin‐6

“…Moreover, the protein levels of MAPK13 and Sirt6 were significantly suppressed by miR-351-5p. Interestingly, some studies have demonstrated that MAPK13 and Sirt6 can regulate oxidant stress, inflammation and apoptosis (Risco et al, 2012;Ikemura et al, 2013;Zhong et al, 2014;Zur et al, 2015). Therefore, miR-351-5p may play important roles in regulating oxidant stress, inflammation and apoptosis, thus controlling II/R damage, by targeting MAPK13 and Sirt6.…”