Pharmacological modulation of NF-κB-dependent COX-2/PGE₂ signaling influences inflammatory lesion development during Leishmania mexicana infection.

Activation of host inflammatory signaling pathways represents a critical determinant of tissue responses during Leishmania infection. Prostaglandin E₂ (PGE₂), synthesized by cyclooxygenase-2 (COX-2), has been implicated in the modulation of macrophage activation and disease pathology; however, the intracellular mechanisms regulating its production in specific host cell contexts remain incompletely defined. In the present study, we investigated the contribution of mitogen-activated protein kinase (MAPK) and NF-κB signaling pathways to the regulation of the COX-2/PGE₂ axis during infection of J774A.1 macrophages with Leishmania mexicana promastigotes. Infection induced rapid and sustained ERK1/2 activation together with increased COX-2 expression and PGE₂ synthesis. In contrast, p38 MAPK activation was delayed and transient, declining rapidly compared with the sustained ERK1/2 response, while JNK phosphorylation remained minimal under the experimental conditions evaluated. Pharmacological inhibition of NF-κB signaling significantly reduced inflammatory mediator production without affecting early parasite internalization. In a BALB/c model of cutaneous leishmaniasis, local administration of the NF-κB inhibitor BAY11-7082 was associated with decreased lesion progression, suggesting that modulation of host inflammatory signaling may influence tissue pathology during infection. In axenic cultures, the compound produced a delayed reduction in parasite proliferation, indicating that potential direct antiparasitic effects may be limited under the experimental conditions evaluated. Overall, these findings support a role for coordinated MAPK and NF-κB activation in the regulation of COX-2-dependent lipid mediator production during L. mexicana infection and highlight the relevance of context-dependent host inflammatory signaling as a complementary factor influencing disease progression.