Expression of IL-33 in the epidermis: The mechanism of induction by IL-17
Introduction
Interleukin (IL)-33 is a novel member of the IL-1 cytokine family, identified as a ligand for the orphan receptor, ST2L (IL-1RL1). At the mRNA level, IL-33 is expressed in many organs [1], whereas the protein is mainly expressed in epithelial and endothelial cells in a constitutive manner [2]. Thus, IL-33 is not mainly produced by immune cells, but rather is constitutively produced by epithelial cells (including keratinocytes) in various tissues and organs. IL-33 polarizes naïve T cells to produce T-helper (Th)-2 associated cytokines [1], functions as a chemo-attractant for Th-2 cells, and also induces secretion of proinflammatory cytokines and chemokines by mast cells, basophils and Th-1 type cytokines from NK and NKT cells [3]. IL-33 is implicated in many diseases, especially those in which Th2-dependent inflammation predominates [4], [5]. IL-33 is primarily produced as a 30 kDa precursor (pro-form), which is digested by proteases, such as caspases and calpains, into 18–20 kDa mature form [6]. IL-33 has dual functions; first, it has been attributed to the epithelial “alarmin” defense system. Pathogen-associated molecular pattern (PAMP) molecules and cytokines such as TNF-α, IL-1β and IFN-γ stimulate the production of IL-33 [7], which is released after cell damage to activate the immune system. Second, as a nuclear protein, it suppresses pro-inflammatory gene transcription [8]. It is believed that IL-33 in the nucleus is a full length pro-form, while IL-33 as a cytokine is a mature form [6].
Psoriasis is a chronic skin disease resulting from the dysregulated interplay between keratinocytes and infiltrating immune cells. It is now considered a mixed Th1 and Th17 cell-mediated autoimmune disease, in which the induction of IFN-γ+ IL-17+ cells is considered to be pathogenic [9]. IL-17 is a key cytokine that plays a critical role in the pathogenesis of psoriasis. This may be due to the co-operation of IL-17 with IFN-γ, TNF-α, IL-22 or other stimuli, which induces inflammatory cytokines, chemokines, antimicrobial peptides, and inflammatory mediators. Overexpression of IL-17 at mRNA and protein levels has been observed in serum and skin lesions of psoriatic patients, but not in normal skin [10], [11]. Treatment of human keratinocytes with IL-17 in combination with TNF-α induces inflammatory genes typical of those associated with psoriasis [12], [13].
IL-33 participates in many acute, chronic inflammatory, as well as autoimmune diseases [5]. IL-33 has been reported to participate in neutrophilic inflammation in psoriasis [14]. We have recently reported that the expression of IL-33 in the skin lesions of psoriasis, as well as lichen planus and atopic dermatitis [15]. Keratinocytes in psoriasis undergo hyperproliferation and altered differentiation, which play a key role in the immune reaction via production of inflammatory mediators such as cytokines. The induction of some chemokines (CXCL1 and CXCL8) by IL-33 in keratinocytes has been reported in previous studies [14], [15]. We have previously shown that IFN-γ induced IL-33 production in cultured keratinocytes, and that combination of IFN-γ with TNF-α caused IL-33 to be mature [15]. Moreover, IL-33 has been reported to induce neutrophil migration and infiltration, and increase IL-17 and TNF-α production [16].
Therefore, we hypothesized that the production of IL-33 might be regulated by cytokines associated with psoriasis, such as IL-17A, as it is a disease associated with Th1/Th17-mediated autoimmunity and highly expresses IL-17A, IFN-γ, and TNF-α. We tested this hypothesis in the present study by observing the effect of IL-17A on the expression of IL-33 in normal human epidermal keratinocytes (NHEKs).
Section snippets
Cell cultures
NHEKs from neonatal foreskin were purchased from Kurabo (Osaka, Japan), and they were cultured in keratinocyte serum-free media (K-SFM; GIBCO, Invitrogen, Carlsbad, CA) supplemented with 40 μg/mL of bovine pituitary extract (BPE; Kyokuto Seiyaku, Tokyo, Japan) and 5 ng/mL of epidermal growth factor (EGF; R&D Systems, Minneapolis, MN). At approximately 80–90% confluence, cells were trypsinized, diluted to a ratio of 1:4, and passaged. Cells passaged 3–6 times were used for this study. Cells were
Expression of IL-33 and ST2 in psoriatic skin disease
In order to investigate the clinical relevance of our study, we first examined the expression pattern of IL-33 and ST2L in skin from normal controls and psoriasis patients. ST2L is the receptor of IL-33, and the antibody we used stains both ST2L and soluble secreted form of ST2. In normal control skin, IL-33 was rarely detected in keratinocytes but staining was observed in endothelial cells. In psoriatic skin disease, a variable intensity of IL-33 staining was observed among 7 cases. IL-33 was
Discussion
IL-17 cytokine family members include IL-17A-F, and their receptors include IL-17RA-RE. IL-17A is the best characterized and most potent Th17 cytokine [21]. We aimed to investigate the role of IL-17A in the regulation of IL-33 in NHEKs. We clearly demonstrated that IL-17A, a cytokine that plays a pivotal role in psoriasis and the response to infectious agents, strongly induced IL-33 expression in a dose- and time-dependent manner. In human umbilical vein endothelial cells, IL-17 has been
Funding
This work was supported by “Research on Measures for Intractable Diseases” Project: matching fund subsidy (H23-028) from Ministry of Health, Labour and Welfare, and by a grant from the Ministry of Education, Science and Culture. This publication was subsidized by the JKA through promotion funds from KEIRIN RACE.
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