MYCOBACTERIAL 65-KILODALTON HEAT-SHOCK PROTEIN INDUCES TUMOR-NECROSIS-FACTOR-ALPHA AND INTERLEUKIN-6, REACTIVE NITROGEN INTERMEDIATES, AND TOXOPLASMASTATIC ACTIVITY IN MURINE PERITONEAL-MACROPHAGES

The 65-kDa heat shock protein (Hsp65) is supposed to play a role in ho st defense against infections with various microbial pathogens and in autoimmune inflammatory disorders, These effects are thought to result mainly from an Hsp65-specific T-lymphocyte-mediated immune response t hat recognizes conserved epitopes. The aim of the present study was to assess whether mycobacterial Hsp65 has a direct effect on resident mu rine peritoneal macrophages, independent of Hsp65-sensitized T lymphoc ytes, Exposure of peritoneal macrophages from naive C57BL/6 mice to th e mycobacterial Hsp65 in vitro induced an enhanced release of tumor ne crosis factor alpha (TNF-alpha) and interleukin 6, These cells also pr oduced large amounts of reactive nitrogen intermediates (RNI) and inhi bited the intracellular proliferation of Toxoplasma gondii. Small amou nts of gamma interferon acted synergistically with Hsp65, Thus, exposu re of murine macrophages to Hsp65 results in activation of these cells , The acquisition of these characteristics by peritoneal macrophages o ccurred in the absence of sensitized T lymphocytes, Addition of anti-T NF-alpha antiserum resulted in an attenuation of the Hsp65-induced rel ease of RNI and toxoplasmastatic activity, indicating that endogenous TNF-alpha is involved in the Hsp65-induced macrophage activation. The conclusion of this study is that in vitro exposure of peritoneal macro phages to the mycobacterial Hsp65 induces the release of proinflammato ry cytokines and RNI and results in inhibition of the intracellular pr oliferation of T, gondii. These effects on murine macrophages occur in dependently of Hsp65-specific T lymphocytes, The proinflammatory effec t of Hsp65 demonstrated in this study suggests that this heat shock pr otein may play a role in the initiation of inflammation that adds to a non-species-specific resistance in the early stages of infections.