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During VL, the protozoan<jats:named-content content-type=\"genus-species\">Leishmania donovani<\/jats:named-content>induces prostaglandin E2 (PGE2) generation within host macrophages to aid parasite survival. PGE2 significantly influences leishmanial pathogenesis, as<jats:named-content content-type=\"genus-species\">L. donovani<\/jats:named-content>proliferation is known to be attenuated in PGE2-inhibited macrophages. Here, we report for the first time that signaling via macrophage Toll-like receptor 2 (TLR2) plays an instrumental role in inducing PGE2 release from<jats:named-content content-type=\"genus-species\">L. donovani<\/jats:named-content>-infected macrophages. This signaling cascade, mediated via the TLR2\u2013phosphatidylinositol 3-kinase (PI3K)\u2013phospholipase C (PLC) signaling pathway, was found to be indispensable for activation of two major enzymes required for PGE2 generation: cytosolic phospholipase A2 (cPLA2) and cyclooxygenase 2 (Cox2). Inhibition of cPLA2, but not secreted phospholipase A2 (sPLA2) or calcium-independent phospholipase A2 (iPLA2), arrested<jats:named-content content-type=\"genus-species\">L. donovani<\/jats:named-content>infection. During infection, cPLA2 activity increased &gt;7-fold in a calcium-dependent and extracellular signal-regulated kinase (ERK)-dependent manner, indicating that elevation of intracellular calcium and ERK-mediated phosphorylation was necessary for<jats:named-content content-type=\"genus-species\">L. donovani<\/jats:named-content>-induced cPLA2 activation. For transcriptional upregulation of cyclooxygenase 2, activation of the calcium-calcineurin-nuclear factor of activated T cells (NFAT) signaling was required in addition to the TLR2-PI3K-PLC pathway. Detailed studies by site-directed mutagenesis of potential NFAT binding sites and chromatin immunoprecipitation (ChIP) analysis revealed that the binding of macrophage NFATc2, at the \u221273\/\u221277 site on the<jats:italic>cox2<\/jats:italic>promoter, induced<jats:named-content content-type=\"genus-species\">L. donovani<\/jats:named-content>-driven<jats:italic>cox2<\/jats:italic>transcriptional activation. Collectively, these findings highlight the contribution of TLR2 downstream signaling toward activation of cPLA2 and Cox2 and illustrate how the TLR2-PI3K-PLC pathway acts in a concerted manner with calcium-calcineurin-NFATc2 signaling to modulate PGE2 release from<jats:named-content content-type=\"genus-species\">L. donovani<\/jats:named-content>-infected macrophages.<\/jats:p>","DOI":"10.1128\/iai.00528-16","type":"journal-article","created":{"date-parts":[[2016,8,2]],"date-time":"2016-08-02T03:05:13Z","timestamp":1470107113000},"page":"2963-2973","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":41,"title":["Leishmania donovani-Induced Prostaglandin E2 Generation Is Critically Dependent on Host Toll-Like Receptor 2\u2013Cytosolic Phospholipase A2 Signaling"],"prefix":"10.1128","volume":"84","author":[{"given":"Amrita","family":"Bhattacharjee","sequence":"first","affiliation":[{"name":"Division of Molecular Medicine, Bose Institute, Kolkata, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saikat","family":"Majumder","sequence":"additional","affiliation":[{"name":"Division of Molecular Medicine, Bose Institute, Kolkata, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shibali","family":"Das","sequence":"additional","affiliation":[{"name":"Division of Molecular Medicine, Bose Institute, Kolkata, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sweta","family":"Ghosh","sequence":"additional","affiliation":[{"name":"Division of Molecular Medicine, Bose Institute, Kolkata, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satabdi","family":"Biswas","sequence":"additional","affiliation":[{"name":"Division of Molecular Medicine, Bose Institute, Kolkata, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Subrata","family":"Majumdar","sequence":"additional","affiliation":[{"name":"Division of Molecular Medicine, Bose Institute, Kolkata, India"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tibs.2013.04.003"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.177.9.6245"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.173.6.4066"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1128\/CMR.18.2.293-305.2005"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.72.5.1848"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmed.2008.08.005"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00281-012-0342-8"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1101029"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2007-0153OC"},{"key":"e_1_3_2_11_2","doi-asserted-by":"crossref","first-page":"5321","DOI":"10.4049\/jimmunol.150.12.5321","article-title":"Prostaglandin E2 differentially modulates cytokine secretion profiles of human T helper lymphocytes","volume":"150","author":"Snijdewint FG","year":"1993","unstructured":"Snijdewint FG, Kalinski P, Wierenga EA, Bos JD, Kapsenberg ML. 1993. 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