IL‐33 is secreted by psoriatic keratinocytes and induces pro‐inflammatory cytokines via keratinocyte and mast cell activation

Abstract

IL-33 is a novel pro-inflammatory cytokine and ligand for the orphan receptor ST2. Although originally defined as an inducer of Th2-mediated responses, IL-33 was recently found to be involved in arthritis, a Th1/Th17-mediated disease. Here, we assessed the ability of IL-33 to promote inflammation via mast cells (MCs) and keratinocytes (KCs) activation in psoriasis. IL-33 resulted elevated in the skin but not in the serum of psoriasis patients. IL-33 was secreted by psoriasis KCs and HaCaT cells after TNF-a stimulation. In HMC-1, TNF-a, but not IL-17, could induce a robust increase in IL-33 expression. In HaCaT cells, TNF-a was able to induce IL-6, MCP-1 and VEGF, and the addition of IL-33 reinforced these increases. TNF-a + IL-33 combination showed similar results in primary KCs and ex vivo skin organ culture. In conclusion, our study suggests that IL-33 may be involved in psoriasis biology via MCs and KCs.

Effect of TNF-α inhibitors on transcriptional levels of pro-inflammatory interleukin-33 and Toll-like receptors-2 and -9 in psoriatic plaques

“…The results support the involvement of innate immune response elements in the pathophysiology of psoriasis, in line with previous studies (12,17,(22)(23)(24)26,27,(32)(33)(34)(35)(36), although some previous studies have reported conflicting results regarding TLR-9 expression in psoriasis (22,34). The activation of IL-33, TLR-2 and TLR-9 in psoriatic plaques may be important since such activation has been previously associated with the activation of NF-κB (12,23,37).…”

“…A member of the interleukin-1 receptor (IL-1R)/TLR superfamily, IL-33, has been recognized as a pro-inflammatory molecule that is predominantly expressed in the nucleus of cells with a barrier function, such as endothelial and epithelial cells (23,24). These cells share a common intracellular domain (TIR domain) that may, through MyD88, initiate a signaling cascade, leading to NF-κB translocation (23).…”

“…IL-33 has been found to be expressed at elevated levels in affected psoriatic skin, compared with healthy skin, and it has also been proposed to represent a novel marker of psoriasis, relative to other inflammatory skin disorders (25)(26)(27)(28). Balato et al (25) recently demonstrated that inflammatory cytokines, such as TNF-α, induce the secretion of IL-33 from immortalized keratinocytes (24) and support the hypothesis that IL-33 has an important role in the effect of anti-TNF therapy on psoriatic skin (25,29).…”

Targeting IL-33 in Autoimmunity and Inflammation

“…Tumor necrosis factor (TNF), but not IL-17, stimulates secretion of IL-33, which induces expression of IL-6, monocyte chemoattractant protein-1, and vascular endothelial growth factor (VEGF) (Balato et al, 2012). However, it appears that the type of cytokines/ chemokines produced by IL-33 may depend on the particular tissue since the extent and type of such mediators varies between sensitized skin and asthmatic airways (Savinko et al, 2013).…”

Mechanisms of 2,4-Dinitrochlorobenzene-induced acute inflammation in Human Papillomavirus type 16 E7 oncoprotein expressing skin

“…To confirm that, we performed experiments in sensitized animals and showed that following DNCB treatment, sensitized K14.E7 skins also displayed significantly enhanced ear swelling, arginase-1 mRNA and arginase activity production compared to non-transgenic skin as observed in non-sensitized mice (Supplementary figure 2.6). Th2 cytokines, which induce arginase-1 expression and hyperinflammatory response in DNCB-treated K14.E7, might therefore be derived from innate immune cells (153,154) or epithelial cells (155). We also detected the induction of prostaglandin E2 synthase in DNCB-treated K14.E7 skin.…”