Epithelial Cells Promote Fibroblast Activation via IL-1α in Systemic Sclerosis

Abstract

Systemic sclerosis (SSc) is a disorder of systemic and dermal fibrosis of uncertain etiology. Recently, we found that SSc epidermis is abnormal, taking on an activated phenotype observed during wound healing and tissue repair. As epithelial-fibroblast interactions are important during wound repair and in fibrosis in general, we investigated further the phenotype of the SSc epidermis, and tested whether the SSc epidermis provides a pro-fibrotic stimulus to fibroblasts. In this study we show that in SSc epidermis keratinocyte maturation is delayed, and wound-associated keratins 6 and 16 are induced, in both involved and clinically uninvolved skin. Phosphorylation array analysis revealed induction of stress-induced mitogen-activated protein kinase signaling and mesenchymal feedback through hepatocyte growth factor/c-Met in SSc epidermis. SSc epidermal cells maintained with normal fibroblasts in three-dimensional co-culture were found to stimulate fibroblasts, leading to contractility and connective tissue growth factor expression. These effects depend on elevation of IL-1alpha by the epidermal cells and induction of endothelin-1 and transforming growth factor-beta in fibroblasts. Antagonism of endogenous IL-1alpha using IL-1 receptor antagonist blocked gel contraction by SSc epidermis. We propose that in SSc, epidermal cells are in a persistently activated state and are able to promote dermal fibrosis. These findings are important because biologic therapies could target epithelial-fibroblast interactions in the disease.

Serum levels of interleukin‐1α in patients with systemic sclerosis

“…11 Furthermore, it was showed that IL-1a plays a role in the autocrine upregulation of matrix metalloproteinase-1 (MMP-1) and tissue inhibitor of MMP-1 in normal human dermal fibroblasts stimulated by monocyte chemoattractant protein-1. 22,23 Second, in SSc patients with normal serum IL-1a levels, contracture of phalanges was significantly observed (P < 0.05). Moreover, percentage of diffusion capacity for carbon monoxide (%DLco) and arthralgia tended to be observed in SSc patients with normal serum IL-1a levels though there was no significant difference (P = 0.056, P = 0.067).…”

Environmental risk factors of systemic sclerosis

“…Diesel exhaust nanoparticles have been shown to be internalized by monocyte-derived macrophages and keratinocytes from healthy subjects, leading to oxidative, pro-fibrotic, and pro-inflammatory processes in normal human skin [71,72]. A recent series has demonstrated that diesel exhaust nanoparticles induced, in vitro, (1) higher mRNA gene expression of metalloproteases 2, 7, 9, and 12; collagen I and III; and vascular endothelial growth factor (VEGF) in SSc fibroblasts than in controls and (2) activation of keratinocytes of patients with diffuse cutaneous SSc with increase of pro-fibrotic cytokines: IL-1α, IL-8, and IL-6 mRNA levels [73]. IL-1α has been reported to be greatly increased in SSc epidermis, and it is speculated to initiate keratinocyte-fibroblast interactions, leading to fibroblast activation [74].…”

Cell-Extracellular Matrix Interactions in Normal and Diseased Skin

“…Fibrosis is a hallmark of many connective tissue diseases, including scleroderma and systemic sclerosis (reviewed by Ihn 2005;Krieg et al 2007;Olson and Soriano 2009). One of the factors expressed by keratinocytes that promotes fibroblast activation in systemic sclerosis is IL1-a (Aden et al 2010).…”