Journal
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
Volume 137, Issue 6, Pages 1863-+Publisher
MOSBY-ELSEVIER
DOI: 10.1016/j.jaci.2015.09.059
Keywords
cells; signal transducer and activator of transcription 3; suppressor of cytokine signaling 3; stem cell factor; IL-6; mastocytosis
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Funding
- Division of Intramural Research Programs of the National Institute of Allergy and Infectious Diseases
- National Heart, Lung, and Blood Institute, National Institutes of Health
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Background: IL-6, levels of which are reported to be increased in association with mastocytosis, asthma, and urticaria, is used in conjunction with stem cell factor to generate CD34(+) cell-derived primary human mast cell (HuMC) cultures. Despite these associations, the effects on and mechanisms by which prolonged exposure to IL-6 alters HuMC numbers and function are not well understood. Objectives: We sought to study the effect of IL-6 on HuMC function, the mechanisms by which IL-6 exerts its effects, and the relationship of these findings to mastocytosis. Methods: HuMCs were cultured in stem cell factor with or without IL-6. Responses to FceRI aggregation and expression of proteases and receptors, including the soluble IL-6 receptor (sIL-6R), were then quantitated. Epigenetic changes in suppressor of cytokine signaling 3 (SOCS3) were determined by using methylation-specific PCR. Serum samples from healthy control subjects and patients with mastocytosis were assayed for IL-6, tryptase, and sIL-6R. Results: IL-6 enhanced mast cell (MC) proliferation, maturation, and reactivity after FceRI aggregation. IL-6 reduced expression of SOCS3, which correlated with methylation of the SOCS3 promoter and increased expression and activation of signal transducer and activator of transcription 3. IL-6 also suppressed constitutive production of sIL-6R, and serum levels of sIL-6R were similarly reduced in patients with mastocytosis. Conclusion: IL-6 increases MC proliferation and formation of a more reactive phenotype enabled by suppressing proteolytic cleavage of sIL-6R from IL-6R and downregulation of the SOCS3 autoinhibitory pathway. We suggest IL-6 blockade might ameliorate MC-related symptoms and pathology in patients with MC-related diseases associated with increased IL-6 levels, including mastocytosis.
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