Abstract
BackgroundDevelopment and function of tissue resident mast cells (MCs) is tightly controlled by various cytokines, most of which belong to the typical T helper (Th) 2-type cytokines such as IL-3 and IL-4. The effects of the Th1-type cytokine IFN-γ on human MCs is less clear.ResultsHere, we analyzed the effects of IFN-γ on tissue-derived, mature human MCs. We found that INF-γ decreases proliferation, without affecting apoptosis in human intestinal MCs cultured in the presence of optimal concentrations of stem cell factor (SCF) or SCF and IL-4. However, in the absence of growth factors or at suboptimal concentrations of SCF, INF-γ promotes survival through inhibition of MC apoptosis. Interestingly, we found that INF-γ has no effect on FcϵRI expression and FcϵRI-mediated release of histamine and leukotriene (LT)C4, while it has profound effects on FcγR expression and activation. We show that intestinal MCs express FcγRI, FcγRIIa, and FcγRIIc, whereas FcγRIIb expression was found in only 40% of the isolates and FcγRIII was never detectable. INF-γ strongly increases FcγRI and decreases FcγRIIa expression. INF-γ-naïve MCs produce LTC4 but fail to degranulate upon crosslinking of surface-bound monomeric IgG. In contrast, INF-γ-treated MCs rapidly release granule-stored histamine in addition to de novo-synthesized LTC4.ConclusionIn summary, we identify INF-γ as an important regulator of tissue-resident human MCs. IFN-γ displays a dual function by blocking extensive MC proliferation, while decreasing apoptosis in starving MCs and enhancing FcγRI expression and activation. These results emphasize the involvement of mucosal MCs in Th1-mediated disorders.
Highlights
Development and function of tissue resident mast cells (MCs) is tightly controlled by various cytokines, most of which belong to the typical T helper (Th) 2-type cytokines such as IL-3 and IL-4
IFN-γ displays a dual function by blocking extensive MC proliferation, while decreasing apoptosis in starving MCs and enhancing FcγRI expression and activation
Besides stem cell factor (SCF), IL-4 is the most potent cytokine inducing MC proliferation and enhancing IgE-dependent mediator release in tissuederived human MCs [7,19]. These findings reveal the complex biology of human MCs, which can only be understood in detail if the results of studies on human MCs derived from different sources are compiled
Summary
Development and function of tissue resident mast cells (MCs) is tightly controlled by various cytokines, most of which belong to the typical T helper (Th) 2-type cytokines such as IL-3 and IL-4. Th2 type cytokines such IL-3, IL-4, IL-5, and IL-9 have been shown to enhance human MC growth, to increase degranulation and to enhance the production of eicosanoids and many cytokines upon FcεRI-crosslinking [1,5,6,7]. These findings mainly explain elevated MC numbers and enhanced activity in Th2 type disorders [1,8]
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