Role of PPARγ in COX-2 Activation in Mycobacterial Pulmonary Inflammation

Abstract

Preliminary studies show that intranasal (i.n.) administration of BCG in mice induces M1 activation of alveolar macrophages (MØ) that increase TNF-α production and cyclooxygenase-2 (COX-2) expression but reduce constitutive peroxisome proliferator-activated receptor gamma (PPARγ) expression. However, COX-2 is catalytically inactive for prostaglandin E2 release, unlike COX-2 active in M1 activation in vitro by BCG. In this study, we determined the role of PPARγ for BCG-induced M1 activation in vivo and in vitro. We found that treatment of mice with GW9662, a PPARγ antagonist, prior to i.n. BCG, partially restored PPARγ expression, and decreased TNF-α production and COX-2 expression. But COX-2 was still inactive. The decreased effects on TNF-α and COX-2 were also observed when alveolar MØ were treated in vitro with GW9662/BCG, but COX-2 was still active. Our results indicate that PPARγ up-regulates M1 activation of alveolar MØ, but inactive COX-2 formation is independent of PPARγ in mycobacterial pulmonary inflammation.

Cholera Toxin Induces a Shift from Inactive to Active Cyclooxygenase 2 in Alveolar Macrophages Activated by Mycobacterium bovis BCG

“…These included (i) mice deficient in methionine sulfoxide reductase A, an enzyme protecting hosts from oxidation, (ii) mice deficient in Flt-1 tyrosine kinase, an enzyme regulating monocyte infiltration, (iii) mice deficient in CRTH2 (chemoattractant receptor-homologous molecule expressed on Th2 cells), a receptor of PGD 2 derived from activated mast cells, and (iv) mice that were treated with GW9662, a PPAR␥ antagonist. Our published (14) and unpublished (data not shown) results, however, showed that alveolar M in these animals still exhibited NE-dissociated COX-2 when activated by i.n. BCG and NE-associated COX-2 when activated in vitro.…”

“…PPAR␥, consisting of the 53-kDa PPAR␥1 subunit and the 57-kDa PPAR␥2 subunit, is constitutively expressed by alveolar M but not alveolar epithelial cells; our previous study (14) indicated that the major PPAR␥ bands were undetectable in the BCGtreated cells. While clearly visualized in the BCG/CT-treated cells, levels were still less than 15% of those seen in the cells treated with CT alone (Fig.…”

“…CT and CTB were purchased from List Biological Lab, Campbell, CA. Groups of mice (6 mice/group) were given 50 l of saline containing 500 g of BCG and 1 g of CT, 500 g of BCG, 1 g of CT, or saline (controls) intranasally at 0 h, and samples were collected at 24 h. The intranasal doses of BCG and CT were based on previous studies (14,34). Alveolar M preparation.…”

“…vaccination of mice with Mycobacterium bovis bacillus Calmette-Guérin (BCG) offered better protection against M. tuberculosis than did systemic vaccination (12). Our previous studies (13,14) indicate that alveolar M, activated by i.n. heatkilled BCG, develop bactericidal M (M1) that facilitate Th1 immunity.…”

PPARγ-activation increases intestinal M1 macrophages and mitigates formation of serrated adenomas in mutant KRAS mice

“…For example, pathogen elimination is facilitated by PPARg-polarized macrophages via enhanced phagocytosis and release of NO, reactive oxygen species, cytotoxic cytokines and altered glucose metabolism (e.g. against Pseudomonas, 36 Mycobacterium, 37 Trypanosoma, 38 Leishmania, 39 Plasmodium 40 and Candida 41 ) in mice and in patients with chronic granulomatous disease (CGD). 42 Nonself recognition of tumors as an "internal pathogen" may be exploited by the same mechanism.…”