Interleukin 4 and prolonged hypoxia induce a higher gene expression of lysyl hydroxylase 2 and an altered cross-link pattern: Important pathogenetic steps in early and late stage of systemic scleroderma?

The major pathological processes of systemic scleroderma (SSc) comprise inflammation and microvascular damage in the early or acute progressive stage as well as tissue fibrosis and hypoxia in the chronic end stage. Fibrosis seems to be a general phenomenon characterized by an increase of hydroxylysine aldehyde derived collagen cross-links which has been shown in vitro for systemic scleroderma fibroblasts. In the present study, we analyzed the cross-link pattern and the gene expression of lysyl hydroxylase 2 (LH2) in the skin of SSc. Furthermore, we determined the modulatory impact of inflammatory cytokines (interleukin 4, TNF- α and interleukin 1α/β) and prolonged hypoxia on the cross-link profile and the gene expression of LH2, respectively. The concentration of hydroxylysine aldehyde derived cross-links was significantly increased in SSc, while the level of lysine aldehyde derived cross-links was not changed. Accordingly, a marked increase of the transcriptional level of LH2 was found. In long term dermal fibroblast cultures, only interleukin 4 induced an increase of hydroxylysine aldehyde derived cross-links accompanied by a higher gene expression of LH2. Furthermore, prolonged hypoxia induced a marked increase of the mRNA level of LH2 in relation to collagen I. The skin of SSc is characterized by an increase of the transcriptional activity of LH2 leading to an altered cross-link pattern. The changes in the quality of the collagenous matrix can also be obtained in cell culture by the exposure of fibroblasts to interleukin 4 or prolonged hypoxia emphasizing the role of this mediator in the acute and the low oxygen tension in the chronic phase of the disease.