Persistent inactivation of macrophage cyclooxygenase-2 in mycobacterial pulmonary inflammation.
The induction of cyclooxygenase-2 (COX-2) in tissue macrophages (MØ) increases prostaglandin E(2) (PGE(2)) release, potentially down-regulating granulomatous inflammation. In response to Mycobacteria, local MØ express COX-2, which is either nuclear envelope (NE)-associated or NE-dissociated. Persistent mycobacterial pulmonary inflammation is characterized by alveolar MØ expressing NE-dissociated (inactive) COX-2 without release of PGE(2). In this study, we examined COX-2 in alveolar MØ after intranasal exposure to heat-killed Mycobacterium bovis BCG (HK-BCG). After administration, whole lungs of C57Bl/6 mice were lavaged with saline; COX-2 expression and PGE(2) release by alveolar MØ and tumor necrosis factor (TNF)-alpha and nitric oxide levels in the lung lavage were monitored. Normal alveolar MØ had undetectable levels of COX-2 on Western blots. However, 1 day after intranasal administration, almost all alveolar MØ had phagocytosed HK-BCG and expressed NE-dissociated COX-2 without any increase in the release of PGE(2). At 28 days after intranasal administration, 68% of alveolar MØ still contained both BCG and the NE-dissociated form of COX-2. NE-associated (active) COX-2 was not observed in alveolar MØ. In contrast, 7 days after intraperitoneal injection of HK-BCG, peritoneal MØ containing HK-BCG were no longer detected. At 28 days after intranasal administration, TNF-alpha and nitrite levels in the lung lavage fluid were significantly higher than those in controls. Our results indicate that mycobacterial pulmonary inflammation is associated with suppressed PGE(2) production by alveolar MØ, with expression of COX-2 dissociated from the NE.
Shinohara
Tsutomu
T
College of Biomedical Sciences, Florida Atlantic University, 777 Glades Rd, PO Box 3091, Boca Raton, FL 33431-0991, USA.
Pantuso
Traci
T
Shinohara
Shizuka
S
Kogiso
Mari
M
Myrvik
Quentin N
QN
Henriksen
Ruth Ann
RA
Shibata
Yoshimi
Y
D000276:Adjuvants, Immunologic; D000280:Administration, Inhalation; D000818:Animals; D001500:BCG Vaccine / Q000008:administration & dosage / Q000276:immunology*; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D002478:Cells, Cultured; D051545:Cyclooxygenase 1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D015232:Dinoprostone / Q000378:metabolism; D004790:Enzyme Induction; D005260:Female; D016753:Interleukin-10 / Q000276:immunology; D016676:Macrophages, Alveolar / Q000166:cytology / Q000201:enzymology* / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009163:Mycobacterium bovis / Q000201:enzymology / Q000276:immunology*; D009569:Nitric Oxide / Q000378:metabolism; D009685:Nuclear Envelope / Q000201:enzymology; D011014:Pneumonia / Q000201:enzymology* / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
D000276:Adjuvants, Immunologic; D001500:BCG Vaccine; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D009569:Nitric Oxide; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D015232:Dinoprostone