IL-4 is a type 2 cytokine that may mediate pleiotropic effects in the NSCLC microenvironment. Here, we investigated whether IL-4 regulates PGE(2) production in NSCLC cells. We found that IL-4 inhibited constitutive COX-2 expression and PGE(2) production in A427 and H2122 NSCLC cell lines, and also suppressed IL-1 beta-induced COX-2 expression in A549 and RH2 NSCLC cell lines. COX-2 mRNA was decreased in response to IL-4, and promoter analysis indicated that IL-4 inhibited both constitutive and IL-1 beta-induced COX-2 transcription. IL-4 inhibited IL-1 beta-stimulated ERK phosphorylation, which may mediate the inhibition of IL-1 beta-induced COX-2 by IL-4. IL-4 did not modulate additional arachidonic acid pathway enzymes mPGES-1 and 15-PGDH, which could potentially be responsible for regulating PGE2 production. Overall, our Studies demonstrate that IL-4 has the capacity to inhibit COX-2 mRNA transcription in NSCLC cells and the inhibition of PGE(2) appears to be predominately COX-2 dependent. (c) 2006 Elsevier Inc. All rights reserved.