SUBTHERAPEUTIC CORTICOSTEROIDS POTENTIATE THE ABILITY OF INTERLEUKIN-10 TO PREVENT CHRONIC INFLAMMATION IN RATS

Background & Aims: Interleukin (IL)-10, which inhibits macrophages and T-helper lymphocyte type 1 (TH1) lymphocytes, attenuates chronic gran ulomatous inflammation induced by bacterial cell wall polymers. This s tudy determines whether corticosteroids enhance the protective effects of IL-10 in cultured peripheral blood mononuclear cells (PBMNCs) and in vivo when started before or after the onset of experimental chronic granulomatous inflammation. Methods: Intestines of Lewis rats were in jected intramurally with streptococcal peptidoglycan-polysaccharide (P G-APS) polymers. Daily murine recombinant IL-10 and/or dexamethasone ( DEX) therapy was started 12 hours before or at several intervals after PG-APS injection. Results: IL-10 plus corticosteroids additively inhi bited IL-1 beta secretion in human PBMNCs but preserved the beneficial IL-1RA/IL-1 beta ratio induced by IL-10. IL-10 started before PG-APS injection significantly attenuated intestinal and extraintestinal infl ammation, with even more pronounced effects in combination with subthe rapeutic doses of DEX. The combination of DEX decreased the effective dose of IL-10 by at least one half. After onset of systemic inflammati on using doses effective for prevention, IL-10 monotherapy had nearly no benefit and DEX plus IL-10 was similar to the mild therapeutic effe ct of DEX alone. Conclusions: The combination of IL-10 and corticoster oids allows lower doses of both agents in preventing chronic intestina l and systemic inflammation. However, timing of IL-10 administration i s a critical variable in regulating inflammation.