Cyclic AMP signaling enhances lipopolysaccharide sensitivity and interleukin-33 production in RAW264.7 macrophages

While it has been suggested that IL-33 plays pathogenic roles in various disorders, the factors that stimulate IL-33 production are poorly characterized. In the present study, the effect of cyclic adenosine monophosphate (cAMP) signaling on IL-33 production in RAW264.7 macrophages in response to various doses of LPS was examined. High-dose LPS treatment induced IL-33 and TNF protein production in RAW264.7 macrophages. In contrast, low-dose LPS failed to induce IL-33 production while significantly inducing TNF production. In the presence of the membrane-permeable cAMP analog 8-Br-cAMP, low-dose LPS induced vigorous IL-33 production. This phenomenon was consistent with amounts of mRNA. Similarly, the cAMP-increasing agent adrenaline also enhanced the sensitivity of RAW264.7 macrophages to LPS as demonstrated by IL-33 production. The protein kinase A (PKA) inhibitor H89 blocked the effects of 8-Br-cAMP and adrenaline on IL-33 production, suggesting that PKA is involved in IL-33 induction. Taken together, cAMP-mediated signaling pathway appears to enhance the sensitivity of RAW264.7 macrophages to LPS with respect to IL-33 production. Our findings suggest that stress events and the subsequent secretion of adrenaline enhance macrophage production via IL-33; this process may be associated with the pathogenesis of various disorders involving IL-33.