IL-33 augments substance P–induced VEGF secretion from human mast cells and is increased in psoriatic skin

Abstract

The peptide substance P (SP) has been implicated in inflammatory conditions, such as psoriasis, where mast cells and VEGF are increased. A relationship between SP and VEGF has not been well studied, nor has any interaction with the proinflammatory cytokines, especially IL-33. Here we report that SP (0.1-10 μM) induces gene expression and secretion of VEGF from human LAD2 mast cells and human umbilical core blood-derived cultured mast cells (hCBMCs). This effect is significantly increased by coadministration of IL-33 (5-100 ng/mL) in both cell types. The effect of SP on VEGF release is inhibited by treatment with the NK-1 receptor antagonist 733,060. SP rapidly increases cytosolic calcium, and so does IL-33 to a smaller extent; the addition of IL-33 augments the calcium increase. SP-induced VEGF production involves calcium-dependent PKC isoforms, as well as the ERK and JNK MAPKs. Gene expression of IL-33 and histidine decarboxylase (HDC), an indicator of mast cell presence/activation, is significantly increased in affected and unaffected (at least 15 cm away from the lesion) psoriatic skin, as compared with normal control skin. Immunohistochemistry indicates that IL-33 is associated with endothelial cells in both the unaffected and affected sites, but is stronger and also associated with immune cells in the affected site. These results imply that functional interactions among SP, IL-33, and mast cells leading to VEGF release contribute to inflammatory conditions, such as the psoriasis, a nonallergic hyperproliferative skin inflammatory disorder with a neurogenic component.inflammation | cytokines | IL-1 | innate immunity | stress

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).…”

“…IL-33 can act as both a pro-and anti-inflammatory factor (38). It is currently considered that biologically active IL-33 is released during necrosis as an endogenous danger or 'alarm' signal; during apoptosis, IL-33 is cleaved and inactivated (3,27). The present results indicate that the pro-inflammatory function of IL-33 in psoriatic skin can be inhibited by TNF-α blockers, in agreement with previous studies by Balato et al (25) and Li et al (39) which have described the regulation of IL33 by TNF-α.…”

“…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).…”

Interleukin-33 plasma levels in patients with relapsing-remitting multiple sclerosis

“…One of the most important cytokines that directly contributes to the immunopathogenesis of MS is IL-33 (17), a recently discovered cytokine, taking part in various inflammatory and autoimmune diseases like psoriasis, lupus erythematous, ulcerative colitis and MS (17)(18)(19)(20). ST2L, a receptor of IL-33, is expressed on the surface of various subsets of leukocytes and conducts signals to activate the MAPK and nuclear factor κB (NF-κB) pathways by TNF receptor-associated factor 6 (TRAF6) (21,22).…”

Connective tissue manipulation: A review of theory and clinical evidence

“…It also activates mast cell secretion, potentially of histamine, nitric oxide, vasoactive intestinal polypeptide (a vasodilator) and heparin. These cells are present in large numbers around blood vessels (Theoharides et al, 2010). An accurate, skilled, CTM fascial stroke will often produce a triple response reaction of reddening and swelling in a line (wheal) but excessive or inaccurate strokes may produce skin irritation and discomfort.…”