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Characterization of immunosuppressive functions of murine peritoneal macrophages induced with various agents
Abstract:
Murine peritoneal macrophages (M phi s), induced with stimuli such as thioglycollate, zymosan A, OK-432, bacille Calmette-Guérin (BCG), or live Mycobacterium intracellulare, showed varying levels of inhibitory activity against the concanavalin A (Con A) blastogenic response of splenic T cells. All test M phi s significantly inhibited the interleukin 2 (IL-2)-producing ability of T cells but this inhibition was not enough to explain the observed reduction in T cell Con A mitogenesis. In contrast, they markedly inhibited IL-2-reactive T cell generation, and the inhibition was sufficient to cause the reduction in T cell mitogenesis. A general relationship was observed between immunosuppressive activity of a given M phi and its active oxygen-producing ability (measured in terms of chemiluminescence) in response to phorbol myristate acetate triggering (r = .84, P less than .005). However, the suppressor activity of test M phi s was not reduced by superoxide dismutase and catalase, indicating that active oxygen radicals themselves did not mediate the expression of the immunosuppressive activity of these M phi s. On the other ahnd, indomethacin (an inhibitor of prostaglandin synthesis) caused a partial reduction in their immunosuppressive activity. The suppressor activity of M phi s induced with intraperitoneal injection of recombinant interferon gamma (IFN-gamma) was markedly reduced in the presence of myoglobin, a scavenger for nitric oxide radical (NO.). Tumor necrosis factor alpha (TNF alpha) failed to affect Con A mitogenesis of splenic T cells, even in combination with IFN-gamma. On the other hand, unsaturated long-chain fatty acids including oleic, linoleic, linolenic, and arachidonic acids markedly reduced the T cell function. These findings suggest some important roles of prostaglandins, NO., and long-chain unsaturated fatty acids as mediators of the expression of immunosuppressive function of the peritoneal M phi s.
Insights
Activated macrophages suppress T cell responses by inhibiting IL-2 reactive T cell generation. Prostaglandins, nitric oxide, and unsaturated fatty acids mediate this immunosuppression, not active oxygen radicals.
Area of Science:
- Immunology
- Cell Biology
Background:
- Murine peritoneal macrophages (M phi s) can exhibit immunosuppressive activity.
- The mechanisms underlying macrophage-mediated T cell suppression are not fully understood.
Purpose of the Study:
- To investigate the mediators responsible for the immunosuppressive activity of activated murine peritoneal macrophages on T cell responses.
Main Methods:
- Macrophages were induced using various stimuli.
- T cell blastogenic response to concanavalin A (Con A) was measured.
- Inhibition of IL-2 production and IL-2-reactive T cell generation was assessed.
- The role of active oxygen species, prostaglandins, nitric oxide (NO.), and fatty acids was evaluated using specific inhibitors and scavengers.
Main Results:
- Activated M phi s significantly inhibited T cell IL-2 production and markedly reduced IL-2-reactive T cell generation.
- Macrophage immunosuppressive activity correlated with active oxygen production but was not mediated by active oxygen radicals.
- Indomethacin partially reduced immunosuppression, while myoglobin significantly reduced suppression induced by interferon gamma (IFN-gamma).
- Unsaturated long-chain fatty acids markedly reduced T cell function.
Conclusions:
- Prostaglandins, NO., and unsaturated long-chain fatty acids are key mediators of macrophage-induced T cell suppression.
- Active oxygen radicals are not the primary mediators of this immunosuppressive effect.