Bidirectional modification of IL-6 expression by angiotensin II in human dermal fibroblasts

Autor: Ulrike Muscha Steckelings, Th. Unger, Jana Reinemund, Metin Artuc, Franziska Rompe
Rok vydání: 2008
Předmět:
Zdroj: Experimental Dermatology. 15:643-648
ISSN: 0906-6705
DOI: 10.1111/j.1600-0625.2006.00439j.x
Popis: Recently, we demonstrated the presence of a complete rennin–angiotensin system in human skin and the up-regulation of angiotensin AT1- and AT2-receptors in cutaneous wounds. However, the characterisation of cutaneous actions of angiotensin II (Ang II) under physiological or pathophysiological conditions is only at the very beginning. It is well established for non-cutaneous tissues that the AT1-receptor (AT1-R) mediates pro-inflammatory actions. The role of the AT2-receptor (AT2-R) is far less understood. In order to look for a putative role of Ang II in cutaneous inflammation, we chose interleukin 6 (Il-6) as a representative inflammation marker. Il-6 expression was studied in response to Ang II with or without co-stimulation by TNFalpha, and it was distinguished between AT1- or AT2-receptor-mediated responses, respectively. Human primary dermal fibroblasts (passage 3–5) were isolated from female thoracic skin derived in the course of cosmetic breast surgery. Fibroblasts were stimulated with Ang II (10−7 M) for 24 h and co-incubated with irbesartan (10–5 M; AT1-receptor antagonist) or PD 123319 (10–5 M; AT2-receptor antagonist), respectively. The same experiment was performed on a second set of cells, additionally treated with TNFalpha (10 ng/ml) in order to stimulate Il-6 expression and to examine the effect of Ang II on elevated Il-6 levels. Moreover, AT2-R mediated effects were determined by incubation of cells with the novel AT2-R agonist Compound 21. Il-6 mRNA was detected by Real-Time-PCR. Ang II stimulated Il-6 expression fivefold. This stimulation could be inhibited by irbesartan, but not by PD 123319. TNFalpha caused a marked increase in Il-6 expression, which could be inhibited by AT2-receptor stimulation (by Ang II in the presence of irbesartan or by Compound 21). The effect of Compound 21 was abrogated by PD 123319. Intracellular signalling leading to the induction of IL-6 expression via the AT1-R seemed to involve the CYP-dependent arachidonic acid metabolite 20-hydroxyeicosatetraenoic acid (20-HETE). A CYP-dependent metabolite involved in the AT2-R mediated effects on IL-6 expression could not be defined. Thus, in human dermal fibroblasts, Il-6 expression is stimulated by TNFalpha and to a lesser extent by Ang II via the AT1-receptor. In contrast, Ang II via the AT2-receptor diminishes TNFalpha-induced Il-6 expression. Consequently, Ang II may be involved in cutaneous inflammation by a dual mechanism: it acts pro-inflammatory via the AT1-receptor and anti-inflammatory via the AT2-receptor.
Databáze: OpenAIRE
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