NDLI: Prostaglandin E2 negatively regulates the production of inflammatory cytokines/chemokines and IL-17 in visceral leishmaniasis.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Ukil, Anindita Biswas, Arunima Mukherjee, Madhuchhanda Saha, Amrita Srivastav, Supriya Das, Pijush K.
Description	Author Affiliation: Saha A ( Department of Biochemistry, University of Calcutta, Kolkata 700019, India); Biswas A ( Infectious Diseases and Immunology Division, Council of Scientific & Industrial Research-Indian Institute of Chemical Biology, Kolkata 700032, India.); Srivastav S ( Infectious Diseases and Immunology Division, Council of Scientific & Industrial Research-Indian Institute of Chemical Biology, Kolkata 700032, India.); Mukherjee M ( Infectious Diseases and Immunology Division, Council of Scientific & Industrial Research-Indian Institute of Chemical Biology, Kolkata 700032, India.); Das PK ( Infectious Diseases and Immunology Division, Council of Scientific & Industrial Research-Indian Institute of Chemical Biology, Kolkata 700032, India.); Ukil A ( Department of Biochemistry, University of Calcutta, Kolkata 700019, India)
Abstract	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-coupled E-series prostanoid (EP) receptors. Among four different EPs (EP1-4), infection upregulated the expression of only EP2, and individual administration of either EP2-specific agonist, butaprost, or 8-Br-cAMP, 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- 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.
ISSN	00221767
e-ISSN	15506606
Journal	The Journal of Immunology
Issue Number	5
Volume Number	193
Language	English
Publisher	The American Association of Immunologists
Publisher Date	2014-09-01
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Chemokines Immunology Dinoprostone Interleukin-17 Leishmania Donovani Leishmaniasis, Visceral Second Messenger Systems T-lymphocytes Animals Cells, Cultured Cyclic Amp Inflammation Pathology Mice Mice, Inbred Balb C Research Support, Non-u.s. Gov't Discipline Immunology
Content Type	Text
Resource Type	Article
Subject	Immunology and Allergy Immunology

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