Abstract
The regulation of interleukin (IL)-6 synthesis by cAMP-increasing agents remains an unresolved issue. Since an increase in cAMP levels via activation of histamine H2 receptors does not induce IL-1 beta synthesis but enhances self-induction of IL-1 (Vannier, E., and Dinarello, C. A. (1993) J. Clin. Invest. 92, 281-287), we investigated whether histamine regulates IL-6 synthesis. Human peripheral blood mononuclear cells were stimulated with IL-1 alpha in the absence or presence of histamine (1 nM to 100 microM). IL-6 was measured using a specific radioimmunoassay. Histamine alone did not induce protein synthesis or mRNA accumulation for IL-6. Histamine (1-100 microM) enhanced IL-1 alpha-induced synthesis of IL-6 (p < 0.001). Cimetidine and ranitidine, H2 receptor antagonists structurally unrelated to each other, completely reversed the histamine-mediated increase in IL-1 alpha-induced IL-6 synthesis. However, diphenhydramine, an H1 receptor antagonist, did not reverse this effect. Prostaglandin E2, an activator of adenylate cyclase, also enhanced IL-1 alpha-induced synthesis of IL-6. Histamine increased and sustained steady-state levels of IL-6 mRNA in IL-1 alpha-stimulated cells, but reduced IL-6 mRNA half-life (3.5 h versus 1.8 h). Our results indicate that cAMP-increasing agents, such as histamine or prostaglandin E2, fail to induce IL-6 synthesis but rather enhance IL-1-induced IL-6 synthesis.
Highlights
From the Department of Medicine, lhfts University School of Medicine a n d New England Medical Centeq Boston, Massachusetts 02111
Histaminein- for both advancedstage melanoma cells and AIDS-relatedKacreased andsustained steady-state levels of IL-6 mRNA posi's sarcoma cells and because both typesof cells proliferate in IL-la-stimulatedcells, but reduced IL-6 mRNA half- in tissues containing numerous mast cells, we investigathteed life (3.5 hversus 1.8 h)
Our results indicate that CAMP- effect of histamine onIL-6 synthesis
Summary
In IL-6 synthesis (36% increase, p < 0.011, whereas cimetidine at 1O"j M failed to reverse the histamine-mediatedincrease in HistamineEnhancesIL-6 Synthesis inIL-la-stimulated IL-6 synthesis (75% increase, p < 0.001). PBMC-After 24 h of culture, unstimulatedPBMC synthesized PGE, Enhances IL-Ia-induced ILS-6ynthesis-Activation of. PBMC stimulated with IL-la (10 H, receptors resultsin increased adenylate cyclase activity ng/ml) synthesized 0.40 2 0.09 ng/ml IL-6 (Fig. 1).Histamine [25]. To strengthen further thheypothesis that increased CAMP alone did not induce IL-6 synthesis (n = 8; data not shown). PGE, alone did not induce observed at higher concentrations of histamianned. Because histamineenhancesIL-la-inducedsynthesis of induced IL-6 synthesis (Fig. 5). The PGE,-mediated increase in IL-lp [19], we investigated whether the histamine-mediated IL-6 synthesis wasdose-dependent. Upon higher concentrations of PGE, further increasedIL-6 synthesis stimulation with IL-la, PBMC synthesized 0.48 2 0.08 ng/ml IL-la-induced synthesis of TNFa ng/ml PGE,; p < 0.001).
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