Mycobacterium tuberculosis–Induced Prostaglandin J₂ and 15-Deoxy-Prostaglandin J₂ Inhibit Inflammatory Signals in Human M1 Macrophages via a Negative Feedback Loop

Tuberculosis caused by Mycobacterium tuberculosis is a leading cause of death globally and a major health concern. In humans, macrophages are the first line invaded by M. tuberculosis. Upon infection, macrophages upregulate cyclooxygenase-2 (COX-2) expression and consequently elevate the formation of PGs, including PGE₂ and PGD₂. Although the role of proinflammatory PGE₂ in M. tuberculosis infection has been reported, the roles of PGJ₂ and 15-deoxy-PGJ₂ (collectively named J₂-PGs), the metabolites of PGD₂ with anti-inflammatory features, remain elusive. In this study, we show that M. tuberculosis (H37Rv strain)–conditioned medium stimulates human monocyte-derived macrophages (MDMs) to elevate COX-2 expression along with robust generation of PGJ₂, exceeding PGD₂ formation, and to a minor extent also of 15-deoxy-PGJ₂. Of interest, in M1-MDM phenotypes, PGJ₂ and 15-deoxy-PGJ₂ decreased M. tuberculosis (H37Rv strain)–conditioned medium–induced COX-2 expression and related PG formation by a negative feedback loop. Moreover, these J₂-PGs downregulated the expression of the proinflammatory cytokines IL-6, IL-1β, and IFN-γ, but elevated the anti-inflammatory cytokine IL-10 and the M2 markers arginase-1 and CD163. These anti-inflammatory effects of J₂-PGs in M1-MDM correlated with impaired activation of TGF-β–activated kinase 1/NF-κB/MAPK pathways. Finally, we found that J₂-PGs regulate COX-2 expression, at least partially, via PGD₂ receptor (DP1) and chemoattractant receptor homologue expressed on Th2 cells/DP2 receptors, but independent of the J₂-PG receptor peroxisome proliferator-activated receptor-γ. Together, our findings reveal that M. tuberculosis induces COX-2 expression in human M1-MDMs, along with robust formation of J₂-PGs that mediates anti-inflammatory effects via a negative feedback loop.