Prostaglandins from Cytosolic Phospholipase A2α/Cyclooxygenase-1 Pathway and Mitogen-activated Protein Kinases Regulate Gene Expression in Candida albicans-infected Macrophages

In Candida albicans-infected resident peritoneal macrophages, activation of group IVA cytosolic phospholipase A(2) (cPLA(2)) by calcium- and mitogen-activated protein kinases triggers the rapid production of prostaglandins I-2 and E-2 through cyclooxygenase (COX)-1 and regulates gene expression by increasing cAMP. In C. albicans-infected cPLA(2)(-/-) or COX-1(-/-) macrophages, expression of Il10, Nr4a2, and Ptgs2 was lower, and expression of Tnf was higher, than in wild type macrophages. Expression was reconstituted with 8-bromo-cAMP, the PKA activator 6-benzoyl-cAMP, and agonists for prostaglandin receptors IP, EP2, and EP4 in infected but not uninfected cPLA(2)(-/-) or COX-1(-/-) macrophages. In C. albicans-infected cPLA(2)(+/+) macrophages, COX-2 expression was blocked by IP, EP2, and EP4 receptor antagonists, indicating a role for both prostaglandin I-2 and E-2. Activation of ERKs and p38, but not JNKs, by C. albicans acted synergistically with prostaglandins to induce expression of Il10, Nr4a2, and Ptgs2. Tnf expression required activation of ERKs and p38 but was suppressed by cAMP. Results using cAMP analogues that activate PKA or Epacs suggested that cAMP regulates gene expression through PKA. However, phosphorylation of cAMP-response element-binding protein (CREB), the cAMP-regulated transcription factor involved in Il10, Nr4a2, Ptgs2, and Tnf expression, was not mediated by cAMP/PKA because it was similar in C. albicans-infected wild type and cPLA(2)(-/-) or COX-1(-/-) macrophages. CREB phosphorylation was blocked by p38 inhibitors and induced by the p38 activator anisomycin but not by the PKA activator 6-benzoyl-cAMP. Therefore, MAPK activation in C. albicans-infected macrophages plays a dual role by promoting the cPLA(2)/prostaglandin/cAMP/PKA pathway and CREB phosphorylation that coordinately regulate immediate early gene expression.