SummaryAmong other effects, prostaglandins (PG) of the E series are known to inhibit several acute and chronic inflammatory conditions in vivo and proinflammatory cytokine production by activated macrophages in culture. The research presented here demonstrates that the inhibitory effect of PGE2 on tumor necrosis factor oe (TNF-oL) and interleukin 6 (IL-6) production by lipopolysaccharide (LPS)-stimulated murine peritoneal macrophages involves IL-10. In a dose-dependent manner, PGE2 inhibits LPS-induced release of TNF-ol and IL-6, but not of lactate or nitric oxide. The decrease in the level of these cytokines is inversely proportional to the increase in immunoreactive IL-10. This differential inhibitory effect of PGE2 is mimicked by agents that elevate intracellular levels of cAMP, but not cGMP. Neutralizing anti IL-10 antibody but not neutralizing antibodies against other macrophage secretory products (IL-6, leukemia inhibitory factor, and transforming growth factor fl [TGF-fl]), significantly reverse the potent inhibitory effect of PGE2. In vivo, the administration of PGE2 before LPS challenge significantly reduces circulating TNF-cr and IL-6 levels. Anti-IL-10 antibody substantially enhanced the LPS-induced TNF-o~ and IL-6 levels in mice that received either LPS alone or LPS plus PGE2. These results suggest that the antiinflammatory effect of PGE2 on mononuclear phagocytes is mediated in part by an autocrine feedback mechanism involving IL-10.M ononuclear phagocytes (macrophages) play a central role in the regulation of immune responses as well as in both acute and chronic inflammation. The mechanisms that participate in these activities are believed to be multifactorial and involve macrophage secretory products (for a review see reference 1). TNF-ol is an important macrophage inflammatory cytokine that mediates a wide range of biologic functions. TNF-c~ is believed to play a major role in septic shock, and to contribute to the pathogenesis of AIDS and several inflammatory and autoimmune diseases (for reviews see references 2, 3). Recently, a number of regulatory factors were described as having the capacity to block macrophage functions, including TNF-cr release. These molecules, also termed "macrophage-deactivating factors;' include PG of the E series (4-8), TGF-3 (9), IL-4 (10), and 12). In addition to their capacity to induce pain, vascular changes and downregulation of T cell functions, PG have been shown to exhibit antiinflammatory properties on macrophages. For example, stimulation of macrophages by LPS or by TNF-c~ induces PGE2 production (13,14), and the addition of PGE2 to LPS-stimulated cells inhibits TNF-c~ mRNA expression and protein secretion (6-8). This information leads to the hypothesis that the release of PG during LPS-induced inflammation constitutes a negative-feedback mechanism that limits the magnitude of inflammatory cytokine production. In vivo, the exogenous administration of PGE suppresses adjuvant arthritis in rats (15), inhibits the manifestation of interstitial nephritis (16), and...

A series of unique indazoles and pyridoindolones have been rationally designed and synthesized as novel classes of cannabinoid ligands based on a proposed bioactive amide conformation. This has led to the discovery of the novel indolopyridone 3a as a conformationally constrained cannabinoid ligand that displays high affinity for the CB2 receptor (K(i)(CB2) = 1.0 nM) and possesses antiinflammatory properties when administered orally in an in vivo murine inflammation model.

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