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Activation of the IL-4 STAT Pathway in Rheumatoid Synovium¹

Ulf Müller-Ladner^*,2, Martin Judex^*, Wibke Ballhorn^*, Frank Kullmann^*, Oliver Distler^*,, Klaus Schlottmann^*, Renate E. Gay, Jürgen Schölmerich^* and Steffen Gay

^* Department of Internal Medicine I, University of Regensburg, Regensburg, Germany; and Center for Experimental Rheumatology, Department of Rheumatology, University Hospital Zürich, Zürich, Switzerland

STATs act as second messenger after binding of a signaling molecule to its receptor. IL-4 STAT is directly involved in the IL-4-dependent gene transcription in the nucleus. We examined the expression and activation of IL-4 STAT and its related kinase Jak-1 in rheumatoid synovium. Rheumatoid arthritis (RA) synovial frozen sections of patients with short-term (<1 year) and long-term disease (>2 years) were examined using in situ hybridization and immunohistochemistry. IL-4 STAT mRNA could be detected in synovium of patients with short-term and long-term RA. The most intensive expression of IL-4 STAT mRNA could be seen in follicular inflammatory infiltrates. In the synovial lining, both fibroblasts and macrophages expressed IL-4 STAT mRNA. IL-4 STAT and Jak-1 protein was expressed by synoviocytes, and up-regulation could be induced after stimulation with IL-4. Activation of IL-4 STAT was reflected by phosphorylation of IL-4 STAT. The results indicate that IL-4 STAT is involved in key pathomechanisms in RA synovium and that IL-4 STAT-dependent pathways operate in early and late stages of the disease and presumably contribute to inhibitory immune mechanisms in RA synovium.

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