Cellular Arachidonate-releasing Function and Inflammation-associated Expression of Group IIF Secretory Phospholipase A2

Makoto Murakami,Kumiko Yoshihara,Satoko Shimbara,Gérald Lambeau,Michael H Gelb,Alan G Singer,Masatsugu Sawada,Naoki Inagaki,Hiroichi Nagai,Motoko Ishihara,Yukio Ishikawa,Toshiharu Ishii,Ichiro Kudo

doi:10.1074/jbc.m112385200

Makoto Murakami, Kumiko Yoshihara + Show 11 more

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https://doi.org/10.1074/jbc.m112385200

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Here we report the cellular arachidonate (AA)-releasing function of group IIF secretory phospholipase A(2) (sPLA(2)-IIF), a sPLA(2) enzyme uniquely containing a longer C-terminal extension. sPLA(2)-IIF increased spontaneous and stimulus-dependent release of AA, which was supplied to downstream cyclooxygenases and 5-lipoxygenase for eicosanoid production. sPLA(2)-IIF also enhanced interleukin 1-stimulated expression of cyclooxygenase-2 and microsomal prostaglandin E synthase. AA release by sPLA(2)-IIF was facilitated by oxidative modification of cellular membranes. Cellular actions of sPLA(2)-IIF occurred independently of the heparan sulfate proteoglycan glypican, which acts as a functional adaptor for other group II subfamily sPLA(2)s. Confocal microscopy revealed the location of sPLA(2)-IIF on the plasma membrane. The unique C-terminal extension was crucial for its plasma membrane localization and optimal cellular functions. sPLA(2)-IIF expression was increased in various tissues from lipopolysaccharide-treated mice and in ears of mice with experimental atopic dermatitis. In human rheumatoid arthritic joints, sPLA(2)-IIF was detected in synovial lining cells, capillary endothelial cells, and plasma cells. These results suggest that sPLA(2)-IIF is a potent regulator of AA metabolism and participates in the inflammatory process under certain conditions.

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Secretory phospholipase A21 comprises a large family of lipolytic enzyme, in which 10 isozymes have been identified in mammals [1, 2]
This enzyme has been implicated in cell growth and death [17], atherosclerosis [18], tumorigenesis [19], degranulation [20], anti-coagulation [21], and defense against bacteria [22,23,24]. Secretory phospholipase A2 (sPLA2)-IIC is highly expressed in rodent testes, but only a pseudogene for this enzyme has been found in the human genome [25]. sPLA2-IID and -IIE are structurally most related to sPLA2-IIA, showing nearly 50% homology to each other (26 –29). sPLA2-IID augments stimulus-induced arachidonic acid (AA) release in a manner similar to sPLA2-IIA [16] and its expression is regulated by proinflammatory stimulus [27]
Since lipid oxidation is one of the key events leading to membrane rearrangement [10, 44, 45] and since the increased AA release by sPLA2-IIA or sPLA2-V transfectants is attenuated by treatment with several antioxidants that inhibit 12/15LOX [10], we examined the effect of nordihydroguaiaretic acid (NDGA), a 12/15-LOXinhibitable antioxidant [10], on the AA-releasing function of sPLA2-IIF

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Secretory phospholipase A2 (sPLA2)1 comprises a large family of lipolytic enzyme, in which 10 isozymes (groups IB, IIA, IIC, IID, IIE, IIF, III, V, X, and XII) have been identified in mammals [1, 2]. HEK293 transfectants were cultured for 4 h, FCS-dependent releases of [3H]AA and [3H]OA by sPLA2-IIF-expressing cells were increased 2- and 1.7-fold, respectively, relative to those by replicate control cells (Fig. 2A).

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