COX-2 inhibition represses the generation of M2 macrophages and slows tumor progression (111.31)

Abstract

Abstract Macrophages (mΦs) are very heterogeneous and include immune-activating (M1) and immune-suppressive (M2) subsets. In response to cytokine or TLR activation, M1-mΦs (killer mΦs) express iNOS, which produces tumoricidal and bacteriocidal nitric oxide (NO). M2-mΦs (healer mΦs), in contrast, express arginase I, which competes with iNOS for L-arginine, to promote cell proliferation and fibrosis. SHIP (SH2-containing inositol-5’ phosphatase), a hematopoietic-specific negative regulator of the PI3K pathway, prevents M2-mΦ development. Thus, in SHIP-/- C57BL/6 mice, all the mΦs are M2 skewed. As a result, subcutaneously injected Lewis lung carcinoma (LLC) tumors grow faster in SHIP-/- than in +/+ mice, and this rapid tumor growth correlates with high tumor-associated arginase. We therefore hypothesize that high PI3K activity skews bone marrow (bm) progenitors to become tumor-promoting M2-mΦs. Herein we show that PGE2 also skews SHIP-/- , but not +/+, bm progenitors to M2 mΦs and that COX-2 inhibitors repress this skewing. Specifically, the COX-2 inhibitor SC-58125 reduces arginase levels and IL-10 production from in vitro derived SHIP-/- bmmΦs. Furthermore, another COX-2 inhibitor, Celebrex, slows tumor growth in vivo, and this correlates with reduced arginase in tumor-associated mΦs. This is consistent with COX-2 inhibitors slowing tumor growth, at least in part, by preventing M2-skewing of tumor-associated mΦs.