Prostaglandin E2 Negatively Regulates the Production of Inflammatory Cytokines/Chemokines and IL-17 in Visceral Leishmaniasis

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-α 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.

Circulating Biomarkers of Immune Activation, Oxidative Stress and Inflammation Characterize Severe Canine Visceral Leishmaniasis

“…Recently, our group has shown the importance of eicosanoids in modulating immune responses in Leishmania infection12. In addition, PGE2 has been shown to contribute to parasite proliferation1116, whereas LTB4 increases macrophage activation and intracellular destruction171819. Therefore, the balance between these two mediators seems to contribute to the control of Leishmania infection and inflammation.…”

Leishmania donovani-Induced Prostaglandin E2 Generation Is Critically Dependent on Host Toll-Like Receptor 2–Cytosolic Phospholipase A2 Signaling

“…It is now well established that L. donovani infection induces PGE2 release from infected macrophages (13,14), which involves upregulation of Cox2. Our lab has previously reported increased Cox2 expression during L. donovani infection (17).…”

“…Human monocytes have exhibited increased PGE2 production following Leishmania infection (13). The importance of PGE2 in the progression of VL is critical, as disease progression is arrested in PGE2-inhibited macrophages (14). This study aimed to elucidate the signaling phenomena responsible for L. donovani-induced PGE2 generation in an attempt to understand which components can be modulated to block its immunosuppressive effects.…”

Prostaglandin I2 Suppresses Proinflammatory Chemokine Expression, CD4 T Cell Activation, and STAT6-Independent Allergic Lung Inflammation

“…Studies have shown that the COX pathway and its downstream lipid mediators regulate chemokine expression in inflammation. Inhibition of COX-2 augmented CCL3 (MIP-1α) and CCL5 (RANTES) expression by Leishmania -infected peritoneal macrophages (24). PGE 2 attenuated LPS-induced mRNA and protein expression of CXCL-10 (IP-10) and CCL3 in mouse adipose tissue (25).…”