Efficient cytokine-induced IL-13 production by mast cells requires both IL-33 and IL-3

Background IL-13 is a critical effector cytokine for allergic inflammation. It is produced by several cell types, including mast cells, basophils, and TH 2 cells. In mast cells and basophils its induction can be stimulated by cross-linkage of immunoglobulin receptors or cytokines. The IL-1 family members IL-33 and IL-18 have been linked to induction of IL-13 production by mast cells and basophils. In CD4 TH 2 cells IL-33–mediated production of IL-13 requires simultaneous signal transducer and activator of transcription (STAT) 5 activation. Objective Here we have addressed whether cytokine-induced IL-13 production in mast cells and basophils follows the same logic as in TH 2 cells: requirement of 2 separate signals. Methods By generating a bacterial artificial chromosome (BAC) transgenic IL-13 reporter mouse, we measured IL-13 production in mast cells and basophils. Results In mast cells harvested from peritoneal cavities, 2 cytokine signals are required for IL-13 production: IL-33 and IL-3. In bone marrow mast cells IL-13 production requires IL-33, but the requirement for a STAT5 inducer is difficult to evaluate because these cells require the continuous presence of IL-3 (a STAT5 activator) for survival. Poorer STAT5 inducers in culture (IL-4 or stem cell factor) result in less IL-13 production on IL-33 challenge, but the addition of exogenous IL-3 enhances IL-13 production. This implies that bone marrow–derived mast cells, like peritoneal mast cells and TH 2 cells, require stimulation both by an IL-1 family member and a STAT5 inducer to secrete IL-13. Basophils follow the same rule; splenic basophils produce IL-13 in response to IL-18 or IL-33 plus IL-3. Conclusion Optimal IL-13 production from mast cells and basophils requires 2 cytokine signals.