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Coordinate Regulation of TLR-Mediated Arachidonic Acid Mobilization in Macrophages by Group IVA and Group V Phospholipase A₂s¹

Instituto de Biología y Genética Molecular, Consejo Superior de Investigaciones Científicas, and Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, Valladolid, Spain

Macrophages can be activated through TLRs for a variety of innate immune responses. In contrast with the wealth of data existing on TLR-dependent gene expression and resultant cytokine production, very little is known on the mechanisms governing TLR-mediated arachidonic acid (AA) mobilization and subsequent eicosanoid production. We have previously reported the involvement of both cytosolic group IVA phospholipase A₂ (cPLA₂) and secreted group V phospholipase A₂ (sPLA₂-V) in regulating the AA mobilization response of macrophages exposed to bacterial LPS, a TLR4 agonist. In the present study, we have used multiple TLR agonists to define the role of various PLA₂s in macrophage AA release via TLRs. Activation of P388D₁ and RAW2647.1 macrophage-like cells via TLR1/2, TLR2, TLR3, TLR4, TLR6/2, and TLR7, but not TLR5 or TLR9, resulted in AA mobilization that appears to involve the activation of both cPLA₂ and sPLA₂ but not of calcium-independent phospholipase A₂. Furthermore, inhibition of sPLA₂-V by RNA interference or by two cell-permeable compounds, namely scalaradial and manoalide, resulted in a marked reduction of the phosphorylation of ERK1/2 and cPLA₂ via TLR1/2, TLR2, TLR3, and TLR4, leading to attenuated AA mobilization. Collectively, the results suggest a model whereby sPLA₂-V contributes to the macrophage AA mobilization response via various TLRs by amplifying cPLA₂ activation through the ERK1/2 phosphorylation cascade.

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.

¹ This work was supported by the Spanish Ministry of Science and Innovation (Grants SAF2007-60055 and BFU2007-67154).

² Address correspondence and reprint requests to Dr. Jesús Balsinde, Instituto de Biología y Genética Molecular, Consejo Superior de Investigaciones Científicas, Calle Sanz y Forés s/n, 47003 Valladolid, Spain. E-mail address: jbalsinde{at}ibgm.uva.es

³ Abbreviations used in this paper: PLA₂, phospholipase A₂; AA, arachidonic acid; cPLA₂, group IVA cytosolic phospholipase A₂; sPLA₂, secreted phospholipase A₂; sPLA₂-V, group V secreted phospholipase A₂; BEL, bromoenol lactone; Pam3SCK4, N-palmitoyl-S-[2,3-bis(palmitoyloxy)-(2R,2S)-propyl]-Cys-[S]-Ser-[S]-Lys(4) trihydrochloride; LTA, lipoteichoic acid from Staphylococcus aureus; FSL-1, S-(2,3-bispalmitoyloxypropyl)-Cys-Gly-Asp-Pro-Lys-His-Pro-Ser-Phe; ODN1826, synthetic oligodeoxynucleotide 1826, 5'-TCCATGACGTTCCTGACGTT-3'; siRNA, small interfering RNA; iPLA₂, calcium-independent phospholipase A₂.

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The JI 2009 182: 3331-3332. [Full Text]  

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