Background/Purpose: Raynaud phenomenon is freaquently observed in patients of systemic sclerosis (SSc) and characterized by episodic vasospasm and ischemia of extremities in response to cold or emotional stress. It has been recogized that cold- or stress-induced norepinephrine (NE) stimulates adrenoreceptor (AR) on pericytes or vascular smooth muscle cells, resulting in vasoconstriction. However, the roles of NE in fibrosis of SSc are not well understood. The aim of this study was to elucidate the role of NE in fibrosis in SSc.

Methods: Protein and mRNA levels of IL-6 and AR expression in normal and SSc fibroblasts treated with or without NE or ARα/β antagonists were measured by ELISA and real-time PCR. The effect of ARβ blocker and ERK inhibitor on NE-induced IL-6 production was analyzed by real-time PCR. The amount of phosphorylation of ERK and total ERK in normal and SSc fibroblasts were measured by Western blot analysis. Proliferation of fibroblasts was determined using the MTS assay.

Results: The serum levels of IL-6 was elevated in patients with early SSc, and correlated with the extent of skin fibrosis. Protein and mRNA levels of IL-6 expression in normal and SSc fibroblasts was increased by NE stimulation in a dose-dependent manner. In addition, NE-induced IL-6 production in SSc fibroblasts was significantly higher than that in normal fibroblasts. The production of IL-6 in fibroblasts was induced by ARβ antagonist, isoproterenol, but not by ARα antagonist, oxymetazoline. ARβ blocker, proplanolol, inhibited NE-induced IL-6 production in normal and SSc fibroblasts, suggesting that NE may induce IL-6 production via ARβ on fibroblasts. There was no change in ARβ expression in normal and SSc fibroblasts treated with or without NE. In addition, proplanolol enhanced NE-induced phosphorylation of ERK, and ERK inhibitor, PD98059, enhanced NE-induced IL-6 production in in normal and SSc fibroblasts, suggesting that NE-induced phosphorylation of ERK via ARα may inhibit NE-induced IL-6 production. Next, we assessed the effect of the treatment with NE and endothelin-1 (ET-1), which is supposed to contribute to the pathogenesis of fibrosis in SSc. Combined treatment with NE and ET-1 resulted in an additive increase in production of IL-6 in SSc fibroblasts. Finally, we identified that NE enhanced proliferation of SSc fibroblasts compared with that of normal fibroblasts.

Conclusion: We conclude that NE enhances IL-6 production and proliferation in SSc fibroblasts via ARβ more than those in normal fibroblasts. Our results indicate that avoidance of cold exposure or emotional stress may attribute to the suppression of fibrosis as well as Raynaud phenomenon in SSc.

---

« Back to 2013 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/norepinephrine-induced-il-6-regulates-fibrosis-in-systemic-sclerosis/