Interferon-γ regulates growth and controls Fcγ receptor expression and activation in human intestinal mast cells

Background: 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. The effects of the Th1-type cytokine IFN-gamma on human MCs is less clear. Results: Here, we analyzed the effects of IFN-gamma on tissue-derived, mature human MCs. We found that INF-gamma 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-gamma promotes survival through inhibition of MC apoptosis. Interestingly, we found that INF-gamma has no effect on Fc epsilon RI expression and Fc epsilon RI-mediated release of histamine and leukotriene (LT)C-4, while it has profound effects on Fc gamma R expression and activation. We show that intestinal MCs express Fc gamma RI, Fc gamma RIIa, and Fc gamma RIIc, whereas Fc gamma RIIb expression was found in only 40% of the isolates and Fc gamma RIII was never detectable. INF-gamma strongly increases Fc gamma RI and decreases Fc gamma RIIa expression. INF-gamma-naive MCs produce LTC4 but fail to degranulate upon crosslinking of surface-bound monomeric IgG. In contrast, INF-gamma-treated MCs rapidly release granule-stored histamine in addition to de novo-synthesized LTC4. Conclusion: In summary, we identify INF-gamma as an important regulator of tissue-resident human MCs. IFN-gamma displays a dual function by blocking extensive MC proliferation, while decreasing apoptosis in starving MCs and enhancing Fc gamma RI expression and activation. These results emphasize the involvement of mucosal MCs in Th1-mediated disorders.