High levels of interleukin 13 in rheumatoid arthritis sera are modulated by tumor necrosis factor antagonist therapy: association with dendritic cell growth activity.

Abstract

To investigate the physiology of interleukin 13 (IL-13) in rheumatoid arthritis (RA) and the effects of tumor necrosis factor (TNF) antagonists (etanercept) on the distribution of IL-13 in patients with RA. We measured cytokine levels in RA sera (pre/post etanercept), RA synovial fluid (SF), osteoarthritis (OA) SF, and normal human sera by ELISA. Detection of IL-13 was not influenced by rheumatoid factor, as revealed in spike recovery and isotype antibody control studies. Biologically active IL-13 in RA SF was studied using dendritic cell (DC) progenitors that develop into mature DC with IL-13 and with neutralizing antibodies to IL-13. The modulation of IL-13 by etanercept was compared to that of IL-6 and monocyte colony stimulating factor (M-CSF). The effect of etanercept on the ability of RA sera to promote DC growth was studied using DC progenitors. IL-13 was increased in RA sera versus normal sera, OA SF, and RA SF. Relative to OA SF and normal sera, RA SF was enriched in IL-13. The IL-13 contained in RA samples was biologically active, prompting DC growth from progenitors. Circulating DC growth activity was strongly reduced by anti-TNF therapy. Whereas decreases in DC growth factors including IL-13 and IL-6 occurred with etanercept therapy and were associated with clinical improvement, concurrent increases in circulating M-CSF (a non-DC, monocyte-specific growth factor) were noted. The increase of biologically active IL-13 in RA supports the concept that IL-13 regulates immune cell (including dendritic cell) activity and indicates how the varied anatomical distribution of cytokines may play a role in the RA disease process. The differential regulation of circulating IL-13 and M-CSF levels by TNF antagonists further implies discrete roles in the TNF-cytokine network in RA.