Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 291, Issue 30, Pages 15588-15601Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M116.734624
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Funding
- Ministry of Education, Culture, Sports, Science and Technology of Japan [15H05905, 16H02613, 26461671, 25460087, 26860051]
- Terumo Foundation
- Takeda Foundation
- Kowa Foundation
- PRIME from Agency for Medical Research and Development
- AMED-CREST from Agency for Medical Research and Development
- Grants-in-Aid for Scientific Research [16H02613, 26461671, 16K15122, 26860051, 15H05905, 16H01372, 25460087] Funding Source: KAKEN
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Phospholipase A(2) 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 A(2) (sPLA(2)-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 omega 3 polyunsaturated fatty acid (PUFA) metabolites, which had the capacity to reduce the expression of pro-inflammatory and Th1/Th17type 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 sPLA(2)-IID as an immunosuppressive sPLA(2) 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.
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