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Secretory Phospholipase A₂-Potentiated Inducible Nitric Oxide Synthase Expression by Macrophages Requires NF-B Activation¹

Suk-Hwan Baek^*, Taeg Kyu Kwon^§, Jun-Hee Lim^*, Yoon-Jeong Lee^*, Hyeun-Wook Chang, Soo-Jung Lee, Jung-Hye Kim^* and Koing-Bo Kwun^2,

Departments of ^* Biochemistry and Molecular Biology, Pharmacy, and Surgery, College of Medicine, Yeungnam University, Taegu, South Korea; and ^§ Department of Immunology, School of Medicine, Keimyung University, Taegu, South Korea.

The effect of secretory group II phospholipase A₂ (sPLA₂) on the expression of the inducible NO synthase (iNOS) and the production of NO by macrophages was investigated. sPLA₂ by itself barely stimulated nitrite production and iNOS expression in Raw264.7 cells. However, in combination with LPS, the effects were synergistic. This potentiation was shown for sPLA₂ enzymes from sPLA₂-transfected stable cells or for purified sPLA₂ from human synovial fluid. The effect of PLA₂ on iNOS induction appears to be specific for the secretory type of PLA₂. LPS-stimulated activation of iNOS was inhibited by the well-known selective inhibitors of sPLA₂ such as 12-epi-scalaradial and -bromophenacyl bromide. In contrast, the cytosolic PLA₂-specific inhibitors methyl arachidonyl fluorophosphate and arachidonyltrifluoromethyl ketone did not affect LPS-induced nitrite production and iNOS expression. Moreover, when we transfected cDNA-encoding type II sPLA₂, we observed that the sPLA₂-transfected cells produced two times more nitrites than the empty vector or cytosolic PLA₂-transfected cells. The sPLA₂-potentiated iNOS expression was associated with the activation of NF-B. We found that the NF-B inhibitor pyrrolidinedithiocarbamate prevented nitrite production, iNOS induction, and mRNA accumulation by sPLA₂ plus LPS in Raw264.7 cells. Furthermore, EMSA analysis of the activation of the NF-B involved in iNOS induction demonstrated that pyrrolidinedithiocarbamate prevented the NF-B binding by sPLA₂ plus LPS. Our findings indicated that sPLA₂, in the presence of LPS, is a potent activator of macrophages. It stimulates iNOS expression and nitrite production by a mechanism that requires the activation of NF-B.

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