Dexamethasone rapidly suppresses IL-33-stimulated mast cell function by blocking transcription factor activity

Abstract

Mast cells are critical effectors of allergic disease and can be activated by IL-33, a proinflammatory member of the IL-1 cytokine family. IL-33 worsens the pathology of mast cell-mediated diseases, but therapies to antagonize IL-33 are still forthcoming. Because steroids are the mainstay of allergic disease treatment and are well known to suppress mast cell activation by other stimuli, we examined the effects of the steroid dexamethasone on IL-33-mediated mast cell function. We found that dexamethasone potently and rapidly suppressed cytokine production elicited by IL-33 from murine bone marrow-derived and peritoneal mast cells. IL-33 enhances IgE-mediated mast cell cytokine production, an activity that was also antagonized by dexamethasone. These effects were consistent in human mast cells. We additionally observed that IL-33 augmented migration of IgE-sensitized mast cells toward antigen. This enhancing effect was similarly reversed by dexamethasone. Simultaneous addition of dexamethasone with IL-33 had no effect on the phosphorylation of MAP kinases or NFκB p65 subunit; however, dexamethasone antagonized AP-1- and NFκB-mediated transcriptional activity. Intraperitoneal administration of dexamethasone completely abrogated IL-33-mediated peritoneal neutrophil recruitment and prevented plasma IL-6 elevation. These data demonstrate that steroid therapy may be an effective means of antagonizing the effects of IL-33 on mast cells in vitro and in vivo, acting partly by suppressing IL-33-induced NFκB and AP-1 activity.

Didox (3,4-dihydroxybenzohydroxamic acid) suppresses IL-33-induced cytokine production in primary mouse mast cells

“…Importantly, therapeutic drugs targeting signals in addition to IgE could be beneficial. For example, IL-33 activation induces TNFα, IL-6, IL-13, MCP-1, MCP-3, and MIP-1α via ST2 signaling cascade in mast cells, which we and others have published [10,15–17]. …”

“…The protocol followed was as previously described [17] using the Amaxa Nucleofector (Lonza, Allendale, NJ). All experiments were performed 48 hours after transfection.…”

Efficacy of long-term intralesional triamcinolone in Morbihan's disease and its possible association with mast cell infiltration

“…Steroids are known to suppress mast cells by inhibiting both their activation and proliferation, as described also for mucosal mast cells in inflammatory bowel disease (Paranjape et al, ; Kang & Kim, ). Additional data are provided by Paranjape et al, who demonstrated recently the inhibitory effects of dexamethasone on mast cell activation by interleukin‐33, including cytokine production, migration, and neutrophil recruitment (Paranjape et al, ). Of major importance for the clinical outcome, seems to be the route of administration, that is, intralesional, considering the poor response of MD to systemic corticosteroids.…”

“…The presence of mast cells in tissue biopsies of these patients, like in our patient, suggests that the effectiveness of triamcinolone may be associated with mast cell infiltration. Steroids are known to suppress mast cells by inhibiting both their activation and proliferation, as described also for mucosal mast cells in inflammatory bowel disease (Paranjape et al, 2016;Kang & Kim, 2002). Additional data are provided by Paranjape et al, who demonstrated recently the inhibitory effects of dexamethasone on mast cell activation by interleukin-33, including cytokine production, migration, and neutrophil recruitment (Paranjape et al, 2016).…”

Didox (3,4-dihydroxybenzohydroxamic acid) suppresses IgE-mediated mast cell activation through attenuation of NFκB and AP-1 transcription

“…The co-transfection protocol utilized a 1:5 ratio of hR luc :NFκB/AP1. The protocol was as previously described [22] using the Amaxa Nucleofector (Lonza, Allendale, NJ). All experiments were performed 48 hours after transfection.…”