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J. Biol. Chem., Vol. 282, Issue 28, 20124-20132, July 13, 2007

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A Novel Role of Group VIB Calcium-independent Phospholipase A₂ (iPLA₂) in the Inducible Expression of Group IIA Secretory PLA₂ in Rat Fibroblastic Cells^*

Hiroshi Kuwata, Chikako Fujimoto, Emiko Yoda, Satoko Shimbara, Yoshihito Nakatani, Shuntaro Hara, Makoto Murakami^¶1, and Ichiro Kudo²

From the Department of Health Chemistry, School of Pharmaceutical Sciences, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, the Tokyo Metropolitan Institute of Medical Science, 3-18-22 Honkomagome, Bunkyou-ku, Tokyo 113-8613, and the ^¶Precursory Research for Embryonic Science and Technology, Japan Science and Technology Agency, 4-1-8 Honcho Kawaguchi, Saitama 332-0012, Japan

Group IIA secretory phospholipase A₂ (sPLA₂-IIA) is a prototypic sPLA₂ enzyme that may play roles in modification of eicosanoid biosynthesis as well as antibacterial defense. In several cell types, inducible expression of sPLA₂ by pro-inflammatory stimuli is attenuated by group IVA cytosolic PLA₂ (cPLA₂) inhibitors such as arachidonyl trifluoromethyl ketone, leading to the proposal that prior activation of cPLA₂ is required for de novo induction of sPLA₂. However, because of the broad specificity of several cPLA₂ inhibitors used so far, a more comprehensive approach is needed to evaluate the relevance of this ambiguous pathway. Here, we provide evidence that the induction of sPLA₂-IIA by pro-inflammatory stimuli requires group VIB calcium-independent PLA₂ (iPLA₂), rather than cPLA₂, in rat fibroblastic 3Y1 cells. Results with small interfering RNA unexpectedly showed that the cytokine induction of sPLA₂-IIA in cPLA₂ knockdown cells, in which cPLA₂ protein was undetectable, was similar to that in replicate control cells. By contrast, knockdown of iPLA₂, another arachidonyl trifluoromethyl ketone-sensitive intracellular PLA₂, markedly reduced the cytokine-induced expression of sPLA₂-IIA. Supporting this finding, the R-enantiomer of bromoenol lactone, an iPLA₂ inhibitor, suppressed the cytokine-induced sPLA₂-IIA expression, whereas (S)-bromoenol lactone, an iPLA₂ inhibitor, failed to do so. Moreover, lipopolysaccharide-stimulated sPLA₂-IIA expression was also abolished by knockdown of iPLA₂. These findings open new insight into a novel regulatory role of iPLA₂ in stimulus-coupled sPLA₂-IIA expression.

Received for publication, December 28, 2006 , and in revised form, May 1, 2007.

^* This work was supported in part by a Showa University special grant-in-aid for Innovative Collaborative Research Projects, and grants-in-aid for Scientific Research from the Ministry of Education, Science, Culture, Sports, and Technology of Japan. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S3 and Table S1.

¹ Supported by Precursory Research for Embryonic Science and Technology from the Japan Science and Technology Agency.

² To whom correspondence should be addressed. Tel.: 81-3-3784-8196; Fax: 81-3-3784-8245; E-mail: ichi-ku{at}pharm.showa-u.ac.jp.

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