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Interleukin-18 has an Important Role in Differentiation and Maturation of Mucosal Mast Cells

Nathan L Sandersa, Sathisha Upparahalli Venkateshaiah, Murli Manohar, Alok K Verma, Hemanth K Kandikattu and Anil Mishra*

A significant amount of correlational evidence has linked increased levels of IL-18 with allergic diseases in both human and animal models, and, as mast cells are major mediators of allergies, we hypothesized that IL-18 may have a role in mast cell biology. Rationale for our hypothesis is based on the evidence that IL-3 deficient mice are not devoid of mast cells, even though IL-3 is a major differentiation and growth factor for mast cells. Accordingly, we cultured IL-18 responsive bone marrow CD34+ cells in vitro under a variety of conditions and cytokine combinations to examine mast cell differentiation and maturation using flow cytometry, quantitative PCR,and immunostaining techniques. Additionally, in vivo mast cell transformation and maturation were also analysed using endogenous IL-18 gene-deficient or Fabpi-IL-18 overexpressed mice. Our data indicate that both IL-3 and IL-18 exposed CD34+ bone marrow precursors differentiate and mature into mast cells. Further, we observed that IL-18 differentiates mast cells independent of IL-3, as pharmacologic blockade of IL-3 does not prevent in vitro IL-18-driven mast cell differentiation. Further, we found that endogenous IL-18 deficiency restricts maturation of IL-3 generated mast cells and IL-18 derived mast cells require IL-3 for their survival. Additionally, we observed IL-18 intestinal overexpression promotes tissue mast cell proliferation and mucosal mast cell development. Taken together, we provide the evidence that IL-18 has an important contributory role in mast cell differentiation, maturation and in vivo development of mucosal mast cells. Therefore, IL-18 may represent a future pharmacologic target for treating mast cell-mediated allergic diseases.