Dehydroepiandrosterone resisted E. Coli O157:H7-induced inflammation via blocking the activation of p38 MAPK and NF-κB pathways in mice

Abstract

Dehydroepiandrosterone (DHEA), a critical metabolite in cholesterol metabolism, can regulate the inflammatory responses in humans or animals. However, the precise mechanisms of these beneficial actions remains poorly understood. Present study aims to clarify the anti-inflammatory function of DHEA and its possible mechanisms in the E. coli O157:H7-stimulated mice. The results indicated that DHEA reduced the mortality of mice and bacterial concentration in the peritoneal fluid in the E. coli-stimulated mice. DHEA increased the spleen index, the activity of lactate dehydrogenase and acid phosphatase; while it decreased the nitric oxide (NO) content and inducible nitric oxide synthase (iNOS) activity in mice. The mRNA levels of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6) and interferon gamma (IFN-γ) were decreased, whereas the interleukin-4 (IL-4) and interleukin-10 (IL-10) mRNA levels were increased in the E. coli-stimulated mice treated with DHEA. Moreover, DHEA treatment reversed the increasing of IFN-γ/IL-4 ratio in mice caused by E. coli infection. Importantly, DHEA blocked the nuclear translocation of p65 through down-regulation the IκB-α protein phosphorylation level in the mice stimulated with E. coli O157:H7. No statically changes were showed on the phospho (p)-ERK1/2 and p-JNK1/2 protein level, while DHEA significantly suppressed the p-p38 protein level in mice. The above results indicated that DHEA alleviated inflammatory responses by suppressing NO secretion and promoting Th2-associated anti-inflammatory cytokines production in mice; and this action might relate to the blocking of p38 MAPK and NF-κB signaling pathways activation. All the above results provide substantial information for understanding the anti-inflammatory function of DHEA and further support it as a potential immunomodulatory in prevention inflammatory and bacterial infection diseases.