Dual Roles of Group IID Phospholipase A2 in Inflammation and Cancer

• Published in: The Journal of biological chemistry 2016-07, Vol.291 (30), p.15588-15601
• Main Authors: Miki, Yoshimi, Kidoguchi, Yuh, Sato, Mariko, Taketomi, Yoshitaka, Taya, Choji, Muramatsu, Kazuaki, Gelb, Michael H., Yamamoto, Kei, Murakami, Makoto
• Format: Article
• Language: English
• Subjects: Animals; Fatty Acids, Omega-3 - genetics; Fatty Acids, Omega-3 - immunology; Group II Phospholipases A2 - genetics; Group II Phospholipases A2 - immunology; Immunity, Cellular; Inflammation - genetics; Inflammation - immunology; Inflammation - pathology; Lipids; Mice; Mice, Knockout; Neoplasm Proteins - genetics; Neoplasm Proteins - immunology; Skin Neoplasms - genetics; Skin Neoplasms - immunology; Skin Neoplasms - pathology; Th1 Cells - immunology; Th1 Cells - pathology; Th17 Cells - immunology; Th17 Cells - pathology
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M116.734624

Phospholipase A2 enzymes have long been implicated in the promotion of inflammation by mobilizing pro-inflammatory lipid mediators, yet recent evidence suggests that they also contribute to anti-inflammatory or pro-resolving programs. Group IID-secreted phospholipase A2 (sPLA2-IID) is abundantly expressed in dendritic cells in lymphoid tissues and resolves the Th1 immune response by controlling the steady-state levels of anti-inflammatory lipids such as docosahexaenoic acid and its metabolites. Here, we show that psoriasis and contact dermatitis were exacerbated in Pla2g2d-null mice, whereas they were ameliorated in Pla2g2d-overexpressing transgenic mice, relative to littermate wild-type mice. These phenotypes were associated with concomitant alterations in the tissue levels of ω3 polyunsaturated fatty acid (PUFA) metabolites, which had the capacity to reduce the expression of pro-inflammatory and Th1/Th17-type cytokines in dendritic cells or lymph node cells. In the context of cancer, however, Pla2g2d deficiency resulted in marked attenuation of skin carcinogenesis, likely because of the augmented anti-tumor immunity. Altogether, these results underscore a general role of sPLA2-IID as an immunosuppressive sPLA2 that allows the microenvironmental lipid balance toward an anti-inflammatory state, exerting beneficial or detrimental impact depending upon distinct pathophysiological contexts in inflammation and cancer.