Heterogeneity of COX-2 macrophages in acute and chronic mycobacterial inflammation (134.30)

Abstract

Abstract Persistent up-regulation of cyclooxygenase-2 (COX-2) and over-production of PGE2 by activated macrophages (MØ) compromise host immunity in cancer immunotherapy, autoimmune diseases, and chronic mycobacterial inflammation such as TB. Previous studies showed that a population of COX-2+ MØ is induced in the spleen of mice given i.p. HK-Mycobacterium bovis BCG. These MØ are derived from radiosensitive immature bone marrow cells that migrate and localize in the spleen. Mature spleen MØ express active COX-2 (subcellularly associated with the nuclear envelope (NE)), and release increased PGE2 from day 5 to day 21 after BCG administration. To determine if local sites of inflammation caused by BCG accumulate similar COX-2+ MØ, C57Bl/6 mice were given i.p. or i.n. BCG (1 and 0.5 mg doses, respectively). We found that 1 - 2 days after i.p. administration, peritoneal and splenic MØ transiently exhibited COX-2 which was dissociated from the NE, inactive, and released no PGE2. However, unlike splenic MØ, neither active nor inactive COX-2 was found in peritoneal MØ over days 3 - 28. After i.n. administration, alveolar MØ persistently expressed inactive COX-2 over days 1 - 28. No alveolar MØ with active COX-2+ were detected. Normal splenic, peritoneal, and alveolar MØ treated in vitro with BCG expressed active COX-2 and increased PGE2 release within 24 h, indicating that in vitro MØ activation does not always mimic in vivo responses. Our results indicate that in vivo BCG preferentially induces active COX-2 in the splenic MØ. In addition, without suppression by PGE2, MØ with inactive COX-2 may be "hyper-active" and regulate tissue-dependent acute and chronic inflammation. (Supported by NIH HL71711, DOD DAMD 17-03-1-0004, BCCRP 06BS-04-9615)