The role of prostaglandin E₂ in the immunopathogenesis of experimental pulmonary tuberculosis

Prostaglandins (PG) are potent mediators of intercellular communication, and PGE₂ at high concentration is immunosuppressive for T-cell-mediated immunity. We studied the kinetics of PGE₂ production and the expression of the enzymes related to its synthesis during the course of experimental pulmonary tuberculosis. Secondly, we analysed the pathological and immunological changes produced by the pharmacological suppression of PG production. In BALB/c mice infected via the trachea with Mycobacterium tuberculosis H37Rv there is an initial phase of partial resistance, dominated by type 1 cytokines plus tumour necrosis factor-α (TNF-α) and expression of the inducible form of nitric oxide synthase (iNOS), followed by a phase of progressive disease. During the early phase of the infection some activated macrophages located in the alveolar-capillary interstitium and in granulomas showed strong PGE₂ immunostaining. However, PGE₂ concentrations were relatively low and stable. Animals in this early phase of infection were treated with niflumic acid, a potent and specific blocker of cyclo-oxygenase 2, the rate-limiting enzyme of PG production. In comparison with control animals, the suppression of PG synthesis produced higher inflammation and expression of TNF-α, interleukin-1α and interferon-γ (IFN-γ), but almost complete disappearance of iNOS expression, which coexisted with a significant increment of bacterial load. The late progressive phase in this experimental model is characterized by progressive pneumonia, small granulomas and diminished expression of IFN-γ, TNF-α and iNOS in coexistence with high expression of IL-4. Strong PGE₂ immunostaining was seen in foamy macrophages localized in the pneumonic areas, and the PGE₂ concentration was four-fold higher in this late phase of infection than during the early phase. When PG production was suppressed in animals suffering advanced phase infection, a significant reduction of pneumonia and bacillus load with striking increment of granuloma size was seen, and the expression of IFN-γ, TNF-α and iNOS was also improved. These findings demonstrate a significant participation of PGE₂ in the pathogenesis of pulmonary tuberculosis, showing that during the early phase of the infection there are low PGE₂ concentrations which contribute to iNOS expression permitting the temporal control of bacillus growth, while the high PGE₂ concentrations during the late phase of the disease contribute to down-regulate cell-mediated immunity, permitting disease progression.