Lipopolysaccharide induction of REDD1 is mediated by two distinct CREB-dependent mechanisms in macrophages

•LPS increases REDD1 expression via CREB activation in macrophages.•CREB is activated by early activation of the p38MAPK/MSK1 axis.•CREB is also phosphorylated by delayed action via the COX-2/PGE2/PKA pathway.•Thus, REDD1 is up-regulated via PKA-dependent and -independent CREB activation. REDD1 is induced by various cellular stresses; however, its expression in response to lipopolysaccharide (LPS) has not been clearly elucidated in immune cells. LPS stimulated CREB-dependent and NF-κB-independent REDD1 expression in macrophages. Early increases in CREB phosphorylation and REDD1 expression at 8h following LPS treatment were blocked by inhibition of p38MAPK and mitogen- and stress-activated protein kinase 1 (MSK1), but not PKA. However, delayed CREB-mediated REDD1 expression at 16h was suppressed by inhibition of cyclooxygenase-2 (COX-2) and PKA. It indicates that LPS induces REDD1 expression by two distinct CREB-mediated mechanisms, the early p38MAPK/MSK1 and the delayed COX-2/PGE2/PKA pathways.