IL-33 induces stronger responses in female mast cells and neutrophils: a role for the JNK pathway.

INTRODUCTION

Allergic diseases exhibit considerable sex-based variations, with greater incidence of allergic asthma, atopic dermatitis, food allergy, and chronic urticaria among adult females. This female dominance may be explained by differences in inflammatory signaling.

METHODS

We used primary mouse mast cells, neutrophils, and eosinophils as well as two mouse models of IL-33-induced inflammation to measure male and female responses to IL-33.

RESULTS

We show that the allergy-associated cytokine IL-33 elicits stronger responses from female mast cells and neutrophils compared to males, both in vitro and in vivo. The greater female response was not due to increased expression or sensitivity of the IL-33 receptor in female cells. Instead, we noted female-selective activation of the JNK pathway in response to IL-33. Male and female mast cells both required the ERK, p38, NF-kB, and AP-1 pathways to produce inflammatory cytokines in response to IL-33. However, inhibiting the JNK pathway selectively reduced IL-33-mediated cytokine production in female mast cells. A mast cell-dependent model of IL-33-induced peritonitis showed that gonadectomy ablated sexual dimorphism in the neutrophil influx response. However, plasma IL-13 levels remained higher in females even among mice lacking sex organs.

DISCUSSION: These data show that IL-33 induces female-dominant mast cell and neutrophil responses, partly via female-selective JNK signaling.