TNF Inhibitors are Produced Spontaneously by Rheumatoid and Osteoarthritic Synovial Joint Cell Cultures: Evidence of Feedback Control of TNF Action

Abstract

We have proposed the hypothesis that tumour necrosis factor alpha (TNF-alpha) has a pivotal role in the pathogenesis of rheumatoid arthritis, based on in vitro observations that in RA synovial joint cell cultures removal of TNF-alpha, inhibited other potentially pathogenic cytokines such as the equally proinflammatory cytokine interleukin 1 (IL-1) and the macrophage activating factor, GM-CSF. Here we describe that in both rheumatoid (RA) and osteoarthritic (OA) synovial cultures there is a homeostatic mechanism to regulate the activities of TNF-alpha. This concept is based on several observations. First in these synovial joint cell cultures the substantial discrepancy between the levels of bioactive and immunoreactive TNF-alpha indicates the presence of an inhibitor. Second, TNF binding proteins are produced spontaneously, which are the soluble variants of surface p75 and p55 TNF receptor. The amount of soluble TNF receptors (sTNF-R) produced varied between cultures; p75 sTNF-R was more abundant than p55 sTNF-R (as detected by ELISA), and both were produced at higher levels by RA synovial joint cells in culture, compared to OA cultures. These TNF binding proteins act as endogenous inhibitors of TNF-alpha, since blocking their activity in synovial joint cell culture supernatants with MoAb to p55 and p75 sTNF-R enhanced their cytotoxic activity in the TNF bioassay. The regulation of production of these sTNF-R in synovial joint cell cultures is important as the balance between TNF-alpha and sTNF-R production may determine the outcome of the inflammatory process.

Association of the course of collagen-induced arthritis with distinct patterns of cytokine and chemokine messenger RNA expression

“…This phenomenon appears to be dose and timing dependent and may explain our observation that TNF mRNA is present in uninvolved paws. In addition, it is possible that TNF may be neutralized by natural inhibitors, such as soluble TNF receptor, which is spontaneously produced by RA synovium (48). Overall, the presence of this third group of cytokine and chemokine mRNA at all stages of disease and in uninvolved joints suggests that they may play an essential role in the inflammatory process but are insufficient to either induce arthritis or to block the inflammatory process.…”

Cytokine Blockade as a New Strategy to Treat Rheumatoid Arthritis

“…48 In synovial fluid, sTNF-R levels are severalfold higher than are those in serum, with levels in RA again higher than those in other forms of arthritis. 49,51,52 In vitro 50 and probably in vivo sTNF-R can regulate effects of TNF relevant to the pathogenesis of RA, but this is not sufficient to neutralize the high levels of bioactive TNF in patients with RA. Nevertheless, the available data provide a sound conceptual basis for strategies to treat RA by pharmacological elevation of sTNF-R levels.…”

“…[46][47][48][49][50][51][52] Such soluble receptors inhibit TNF action by competing with cell surface receptors for binding of TNF, thereby blocking the biologic effects of TNF. 48,50 Patients with RA have circulating levels of sTNF-R that are higher (generally 2-6 ng/mL for each type of sTNF-R) than those in sera of healthy individuals, patients with osteoarthritis, or even patients with other forms of inflammatory arthritis 49,51,52 and that are similar to circulating levels of sTNF-R in critically ill patients with hemorrhagic shock or sepsis. 48 In synovial fluid, sTNF-R levels are severalfold higher than are those in serum, with levels in RA again higher than those in other forms of arthritis.…”

Important immunoregulatory role of interleukin-11 in the inflammatory process in rheumatoid arthritis

“…This pathologic process is partly counterbalanced by the production of mediators with antiinflammatory activities, such as TL-10 (3), and cytokine inhibitors, including soluble TNF receptors (4) and the IL-1 receptor antagonist (IL-1Ra) (5). The precise role of other cytokines abundantly detectable in RA joints, such as TL-6 and transforming growth factor P (TGFP), remains a subject of controversy (6,7).…”