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Background  The aberrant expression of CD40, a co-stimulatory receptor found on the antigen-presenting cells, is involved in the pathogenesis of various degenerative diseases. Our previous study demonstrated that the reduction of cytosolic phospholipase A 2  alpha (cPLA 2 α) protein overexpression and activation in the spinal cord of a mouse model of ALS, hmSOD1 G93A, inhibited CD40 upregulation in microglia. The present study was designed to determine whether cPLA 2 α has a direct, participatory role in the molecular events leading to CD40 induction.    Methods  Cultures of primary mouse microglia or BV-2 microglia cell line exposed to lipopolysaccharide (LPS) or interferon gamma (IFNγ) for different periods of time, in order to study the role of cPLA 2 α in the events leading to CD40 protein induction.    Results  Addition of LPS or IFNγ caused a significant upregulation of cPLA 2 α and of CD40, while prevention of cPLA 2 α upregulation by a specific oligonucleotide antisense (AS) prevented the induction of CD40, suggesting a role of cPLA 2 α in the induction of CD40. Addition of LPS to microglia caused an immediate activation of cPLA 2 α detected by its phosphorylated form, while addition of IFNγ induced cPLA 2 α activation at a later time scale (4 h). The activation of cPLA 2 α is mediated by ERK activity. Suppression of cPLA 2 α activity inhibited superoxide production by NOX2-NADPH oxidase and activation of NF-κB detected by the phosphorylation of p65 on serine 536 at 15 min by LPS and at 4 h by IFNγ. Inhibition of NOX2 prevented NF-κB activation and CD40 induction but did not affect cPLA 2 α activation, suggesting cPLA 2 α is located upstream to NOX2 and NF-κB. The activation of cPLA 2  by LPS was mediated by both adaptor proteins downstream to LPS receptor; TRIF and MyD88, while the activation of cPLA 2 α by IFNγ was mediated by the secreted TNF-α at 4 h. The early activation of STAT1α (detected by phospho-serine727 and phoshpo-tyrosine701) by IFNγ and the late activation of STAT1α by LPS were not affected in the presence of cPLA 2 α inhibitors, indicating that STAT1α is not under cPLA 2 α regulation.    Conclusions  Our results show for the first time that cPLA 2  upregulates CD40 protein expression induced by either LPS or IFNγ, and this regulatory effect is mediated via the activation of NOX2-NADPH oxidase and NF-κB. Cumulatively, our results indicate that cPLA 2 α may serve as a pivotal amplifier of the inflammatory response in the CNS.

Regulatory role of cytosolic phospholipase A2 alpha in the induction of CD40 in microglia