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.