Repurposing FDA-approved drugs to inhibit IL-33 mediated mast cell function

Abstract

Abstract IL-33 is an IL-1-family cytokine that is released from fibroblasts, epithelial, endothelial, and some immune cells in response to tissue damage or inflammatory signals. IL-33 activates mast cells, innate leukocytes that play a key role in asthma. IL-33 induces production of inflammatory cytokines that worsen allergic diseases like asthma. It is essential to better understand IL-33 function and how to suppress it. Computer modeling studies using the SYBYL and GOLD algorithms to screen 3035 FDA-approved drugs for interactions with the IL-33 receptor, ST2, at the IL-33 binding site revealed several potential ST2 antagonists. In this study, we show that mouse bone marrow derived mast cells (BMMCs) treated with the antiviral drug lopinavir had diminished IL-33 responsiveness. Specifically, lopinavir (15mM) significantly reduced IL-33-mediated IL-6 and IL-13 secretion. Lopinavir effects noted when the drug was given simultaneously with IL-33 and were maximal when given 1 hour prior to IL-33 and suppression. These rapid effects suggest a direct drug-receptor interaction. We treated BMMCs with drug for up to 24 hours to assess for alternative mechanisms such as ST2 down-regulation, which was not noted. Other candidate drugs included clindamycin, which had no effect on IL-33-mediated cytokine production, and ritonavir and cobcistat, which increased cytokine secretion. Our data demonstrate that lopinavir can inhibit IL-33 mediated mast cell function, likely as an off-target effect of the drug. These data support further investigation of lopinavir and suggest the utility of repurposing FDA-approved drugs in allergy and asthma treatment.