Regulation of IL-1-induced selective IL-6 release from human mast cells and inhibition by quercetin

1 Mast cells are involved in allergic reactions, but also in innate immunity and inflammation. Crosslinkage of mast cell Fc immunoglobulin E receptors (Fc epsilon RI) by multivalent antigen triggers secretion of granule-stored mediators, as well as de novo synthesis of cytokines, including interleukin (IL)-6. 2 We showed recently that the proinflammatory cytokine IL-1 stimulates human leukemic mast cells (HMC-1) and human umbilical cord blood-derived cultured mast cells (hCBMCs) to release newly synthesized IL-6 without tryptase in the absence of degranulation. 3 Here, we investigated several signal-transduction pathways activated by IL-1 leading to IL-6 production by HMC-1 and hCBMCs. 4 We also investigated the effect of the flavonol quercetin that was recently shown to strongly inhibit IL-6 secretion in response to allergic stimulation from hCBMCs. 5 IL-1 stimulated p38, but did not activate extracellular signal-regulated kinase (ERK) or c-jun N-terminal kinase (JNK); it also did not activate protein kinase C(PKC) isozymes alpha, beta, mu and zeta, except for PKC-gamma, which was phosphorylated. 6 The p38 inhibitor SB203580 and the PKC inhibitors Calphostin C and Go6976 completely inhibited IL-1-induced IL-6 production. 7 Quercetin 1-100 mu M inhibited IL-1-induced IL-6 secretion, p38 and PKC-theta phosphorylation in a dose-dependent manner. 8 These results indicate that IL-1-stimulated IL-6 production from human mast cells is regulated by biochemical pathways distinct from IgE-induced degranulation and that quercetin can block both IL-6 secretion and two key signal transduction steps involved.