{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T17:52:05Z","timestamp":1789753925220,"version":"4.0.1"},"reference-count":53,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2014,9,1]],"date-time":"2014-09-01T00:00:00Z","timestamp":1409529600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2014,9,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Persistence of intracellular infection depends on the exploitation of factors that negatively regulate the host immune response. In this study, we elucidated the role of macrophage PGE2, an immunoregulatory lipid, in successful survival of Leishmania donovani, causative agent of the fatal visceral leishmaniasis. PGE2 production was induced during infection and resulted in increased cAMP level in peritoneal macrophages through G protein\u2013coupled E-series prostanoid (EP) receptors. Among four different EPs (EP1\u20134), infection upregulated the expression of only EP2, and individual administration of either EP2-specific agonist, butaprost, or 8-Br\u2013cAMP, a cell-permeable cAMP analog, promoted parasite survival. Inhibition of cAMP also induced generation of reactive oxygen species, an antileishmanial effector molecule. Negative modulation of PGE2 signaling reduced infection-induced anti-inflammatory cytokine polarization and enhanced inflammatory chemokines, CCL3 and CCL5. Effect of PGE2 on cytokine and chemokine production was found to be differentially modulated by cAMP-dependent protein kinase A (PKA) and exchange protein directly activated by cAMP (EPAC). PGE2-induced decreases in TNF-\u03b1 and CCL5 were mediated specifically by PKA, whereas administration of brefeldin A, an EPAC inhibitor, could reverse decreased production of CCL3. Apart from modulating inflammatory\/anti-inflammatory balance, PGE2 inhibited antileishmanial IL-17 cytokine production in splenocyte culture. Augmented PGE2 production was also found in splenocytes of infected mice, and administration of EP2 antagonist in mice resulted in reduced liver and spleen parasite burden along with host-favorable T cell response. These results suggest that Leishmania facilitates an immunosuppressive environment in macrophages by PGE2-driven, EP2-mediated cAMP signaling that is differentially regulated by PKA and EPAC.<\/jats:p>","DOI":"10.4049\/jimmunol.1400399","type":"journal-article","created":{"date-parts":[[2014,7,22]],"date-time":"2014-07-22T02:38:42Z","timestamp":1405996722000},"page":"2330-2339","source":"Crossref","is-referenced-by-count":69,"title":["Prostaglandin E2 Negatively Regulates the Production of Inflammatory Cytokines\/Chemokines and IL-17 in Visceral Leishmaniasis"],"prefix":"10.1093","volume":"193","author":[{"given":"Amrita","family":"Saha","sequence":"first","affiliation":[{"name":"Department of Biochemistry, University of Calcutta , Kolkata 700019 ,","place":["India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arunima","family":"Biswas","sequence":"additional","affiliation":[{"name":"Infectious Diseases and Immunology Division, Council of Scientific & Industrial Research\u2013Indian Institute of Chemical Biology , Kolkata 700032 ,","place":["India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Supriya","family":"Srivastav","sequence":"additional","affiliation":[{"name":"Infectious Diseases and Immunology Division, Council of Scientific & Industrial Research\u2013Indian Institute of Chemical Biology , Kolkata 700032 ,","place":["India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madhuchhanda","family":"Mukherjee","sequence":"additional","affiliation":[{"name":"Infectious Diseases and Immunology Division, Council of Scientific & Industrial Research\u2013Indian Institute of Chemical Biology , Kolkata 700032 ,","place":["India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pijush K","family":"Das","sequence":"additional","affiliation":[{"name":"Infectious Diseases and Immunology Division, Council of Scientific & Industrial Research\u2013Indian Institute of Chemical Biology , Kolkata 700032 ,","place":["India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anindita","family":"Ukil","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, University of Calcutta , Kolkata 700019 ,","place":["India"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2014,9,1]]},"reference":[{"key":"2025030707313389300_r1","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1016\/j.biocel.2009.09.015","article-title":"Prostaglandin E2 at new glance: novel insights in functional diversity offer therapeutic chances","volume":"42","author":"Legler","year":"2010","journal-title":"Int. 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Med."},{"key":"2025030707313389300_r5","doi-asserted-by":"crossref","first-page":"55176","DOI":"10.1074\/jbc.M409816200","article-title":"A novel signaling pathway mediates the inhibition of CCL3\/4 expression by prostaglandin E2","volume":"279","author":"Jing","year":"2004","journal-title":"J. Biol. Chem."},{"key":"2025030707313389300_r6","doi-asserted-by":"crossref","first-page":"5380","DOI":"10.1016\/S0021-9258(18)60727-6","article-title":"Prostaglandin E2 regulates macrophage-derived tumor necrosis factor gene expression","volume":"263","author":"Kunkel","year":"1988","journal-title":"J. Biol. Chem."},{"key":"2025030707313389300_r7","doi-asserted-by":"crossref","first-page":"1092","DOI":"10.4049\/jimmunol.177.2.1092","article-title":"Prostaglandin E2 augments IL-10 signaling and function","volume":"177","author":"Cheon","year":"2006","journal-title":"J. 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Physiol."},{"key":"2025030707313389300_r11","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1016\/S0031-6997(25)06784-5","article-title":"International Union of Pharmacology classification of prostanoid receptors: properties, distribution, and structure of the receptors and their subtypes","volume":"46","author":"Coleman","year":"1994","journal-title":"Pharmacol. Rev."},{"key":"2025030707313389300_r12","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1124\/mol.105.011833","article-title":"Differential regulation of phosphorylation of the cAMP response element-binding protein after activation of EP2 and EP4 prostanoid receptors by prostaglandin E2","volume":"68","author":"Fujino","year":"2005","journal-title":"Mol. 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Immunol."},{"key":"2025030707313389300_r27","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1189\/jlb.0909644","article-title":"MAPK-directed phosphatases preferentially regulate pro- and anti-inflammatory cytokines in experimental visceral leishmaniasis: involvement of distinct protein kinase C isoforms","volume":"88","author":"Kar","year":"2010","journal-title":"J. Leukoc. Biol."},{"key":"2025030707313389300_r28","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1128\/CMR.18.2.293-305.2005","article-title":"Subversion mechanisms by which Leishmania parasites can escape the host immune response: a signaling point of view","volume":"18","author":"Olivier","year":"2005","journal-title":"Clin. Microbiol. Rev."},{"key":"2025030707313389300_r29","doi-asserted-by":"crossref","first-page":"11613","DOI":"10.1074\/jbc.R600038200","article-title":"Prostaglandin E receptors","volume":"282","author":"Sugimoto","year":"2007","journal-title":"J. Biol. Chem."},{"key":"2025030707313389300_r30","doi-asserted-by":"crossref","first-page":"4496","DOI":"10.1158\/0008-5472.CAN-05-0129","article-title":"The prostaglandin E2 receptor EP2 is required for cyclooxygenase 2-mediated mammary hyperplasia","volume":"65","author":"Chang","year":"2005","journal-title":"Cancer Res."},{"key":"2025030707313389300_r31","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1089\/jop.1998.14.293","article-title":"Prostaglandin-stimulated adenylyl cyclase activity via a pharmacologically defined EP2 receptor in human nonpigmented ciliary epithelial cells","volume":"14","author":"Crider","year":"1998","journal-title":"J. Ocul. Pharmacol. Ther."},{"key":"2025030707313389300_r32","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/0162-3109(87)90025-7","article-title":"Modulation of T cells by cyclic AMP in murine influenza virus infection. I. 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Res."},{"key":"2025030707313389300_r35","doi-asserted-by":"crossref","first-page":"8111","DOI":"10.4049\/jimmunol.177.11.8111","article-title":"Cyclooxygenase-2 gene transcription in a macrophage model of inflammation","volume":"177","author":"Kang","year":"2006","journal-title":"J. Immunol."},{"key":"2025030707313389300_r36","doi-asserted-by":"crossref","first-page":"317","DOI":"10.4161\/oxim.2.5.9657","article-title":"cAMP activates the generation of reactive oxygen species and inhibits the secretion of IL-6 in peripheral blood mononuclear cells from type 2 diabetic patients","volume":"2","author":"Isoni","year":"2009","journal-title":"Oxid. Med. Cell. Longev."},{"key":"2025030707313389300_r37","doi-asserted-by":"crossref","first-page":"1058","DOI":"10.1128\/iai.62.3.1058-1063.1994","article-title":"Th1 and Th2 cell-associated cytokines in experimental visceral leishmaniasis","volume":"62","author":"Miralles","year":"1994","journal-title":"Infect. Immun."},{"key":"2025030707313389300_r38","doi-asserted-by":"crossref","first-page":"343961","DOI":"10.4061\/2011\/343961","article-title":"Evasion of host defence by Leishmania donovani: subversion of signaling pathways","volume":"2011","author":"Shadab","year":"2011","journal-title":"Mol. Biol. Int."},{"key":"2025030707313389300_r39","doi-asserted-by":"crossref","first-page":"819512","DOI":"10.1155\/2012\/819512","article-title":"Host cell signalling and leishmania mechanisms of evasion","volume":"2012","author":"Shio","year":"2012","journal-title":"J. Trop. Med."},{"key":"2025030707313389300_r40","doi-asserted-by":"crossref","first-page":"2372","DOI":"10.4049\/jimmunol.1000838","article-title":"Inducible cyclooxygenase released prostaglandin E2 modulates the severity of infection caused by Streptococcus pyogenes","volume":"185","author":"Goldmann","year":"2010","journal-title":"J. Immunol."},{"key":"2025030707313389300_r41","doi-asserted-by":"crossref","first-page":"902","DOI":"10.4049\/jimmunol.138.3.902","article-title":"Experimental cutaneous leishmaniasis. II. A possible role for prostaglandins in exacerbation of disease in Leishmania major-infected BALB\/c mice","volume":"138","author":"Farrell","year":"1987","journal-title":"J. Immunol."},{"key":"2025030707313389300_r42","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1002\/jlb.58.2.217","article-title":"Effect of PGE2 and of agents that raise cAMP levels on macrophage activation induced by IFN-gamma and TNF-alpha","volume":"58","author":"Mau\u00ebl","year":"1995","journal-title":"J. Leukoc. Biol."},{"key":"2025030707313389300_r43","first-page":"130","article-title":"Regulation of Leishmania populations within the host. II. Genetic control of acute susceptibility of mice to Leishmania donovani infection","volume":"30","author":"Bradley","year":"1977","journal-title":"Clin. Exp. Immunol."},{"key":"2025030707313389300_r44","first-page":"231","article-title":"Malaria infections in different strains of mice and their correlation with natural killer activity","volume":"57","author":"Eugui","year":"1979","journal-title":"Bull. World Health Organ."},{"key":"2025030707313389300_r45","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1046\/j.1365-2249.2002.01874.x","article-title":"Differential susceptibility to acute Trypanosoma cruzi infection in BALB\/c and C57BL\/6 mice is not associated with a distinct parasite load but cytokine abnormalities","volume":"128","author":"Roggero","year":"2002","journal-title":"Clin. Exp. Immunol."},{"key":"2025030707313389300_r46","doi-asserted-by":"crossref","first-page":"2457","DOI":"10.4049\/jimmunol.1300786","article-title":"Intrauterine group A streptococcal infections are exacerbated by prostaglandin E2","volume":"191","author":"Mason","year":"2013","journal-title":"J. Immunol."},{"key":"2025030707313389300_r47","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1111\/pim.12011","article-title":"Prostaglandin E\u2082 receptors have differential effects on Leishmania major infection","volume":"35","author":"Penke","year":"2013","journal-title":"Parasite Immunol."},{"key":"2025030707313389300_r48","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1165\/rcmb.2008-0091TR","article-title":"Cyclic AMP: master regulator of innate immune cell function","volume":"39","author":"Serezani","year":"2008","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"2025030707313389300_r49","doi-asserted-by":"crossref","first-page":"2610","DOI":"10.1111\/j.1462-5822.2007.00982.x","article-title":"Malaria circumsporozoite protein inhibits the respiratory burst in Kupffer cells","volume":"9","author":"Usynin","year":"2007","journal-title":"Cell. Microbiol."},{"key":"2025030707313389300_r50","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1007\/BF02602952","article-title":"The role of chemokines in inflammation","volume":"26","author":"Proost","year":"1996","journal-title":"Int. J. Clin. Lab. Res."},{"key":"2025030707313389300_r51","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1111\/j.1365-3083.2007.02025.x","article-title":"Induction of host protective Th1 immune response by chemokines in Leishmania donovani-infected BALB\/c mice","volume":"66","author":"Dey","year":"2007","journal-title":"Scand. J. Immunol."},{"key":"2025030707313389300_r52","doi-asserted-by":"crossref","first-page":"2111","DOI":"10.1074\/jbc.M110.154971","article-title":"Tumor-secreted PGE2 inhibits CCL5 production in activated macrophages through cAMP\/PKA signaling pathway","volume":"286","author":"Qian","year":"2011","journal-title":"J. Biol. 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