Cytokine receptors exist in membrane-bound and soluble forms. They bind their ligands with comparable affinity. Although most soluble receptors are antagonists because they compete with their membrane counterparts for their ligands, some soluble receptors are agonists. In this case, on target cells, the complex of cytokine and soluble cytokine receptor binds to a second receptor subunit and initiates intracellular signal transduction. The soluble receptors of the interleukin-6 (IL-6) family of cytokines--soluble IL-6 receptor (sIL-6R), sIL-11R, and soluble ciliary neurotrophic factor receptor (sCNTFR)--are agonists. In vivo, the IL-6/sIL-6R complex stimulates several types of target cells not stimulated by IL-6 alone, as they do not express the membrane- bound IL-6R. This process has been named transsignaling. We have shown recently that in several chronic inflammatory diseases, such as chronic inflammatory bowl disease, peritonitis, and rheumatoid arthritis, as well as in colon cancer, transsignaling via the sIL-6R complexed to IL-6 is a crucial point in the maintenance of the disease. The mechanism by which the IL-6/sIL-6R complex regulates the inflammatory or neoplastic state is discussed.

Studies in IL-6-deficient (IL-6−/−) mice highlight that IL-6 contributes to arthritis progression. However, the molecular mechanism controlling its activity in vivo remains unclear. Using an experimental arthritis model in IL-6−/− mice, we have established a critical role for the soluble IL-6R in joint inflammation. Although intra-articular administration of IL-6 itself was insufficient to reconstitute arthritis within these mice, a soluble IL-6R-IL-6 fusion protein (HYPER-IL-6) restored disease activity. Histopathological assessment of joint sections demonstrated that HYPER-IL-6 increased arthritis severity and controlled intrasynovial mononuclear leukocyte recruitment through the CC-chemokine CCL2. Activation of synovial fibroblasts by soluble IL-6R and IL-6 emphasized that these cells may represent the source of CCL2 in vivo. Specific blockade of soluble IL-6R signaling in wild-type mice using soluble gp130 ameliorated disease. Consequently, soluble IL-6R-mediated signaling represents a promising therapeutic target for the treatment of rheumatoid arthritis.

Human HtrA1 belongs to a widely conserved family of serine proteases involved in various aspects of protein quality control and cell fate. Although HtrA1 has been implicated in the pathology of several diseases, its precise biological functions remain to be established. Through identification of potential HtrA1 targets, studies presented herein propose that within the context of arthritis pathology HtrA1 contributes to cartilage degradation. Elevated synovial HtrA1 levels were detected in fluids obtained from rheumatoid and osteoarthritis patients, with synovial fibroblasts identified as a major source of secreted HtrA1. Mass spectrometry analysis of potential HtrA1 substrates within synovial fluids identified fibronectin as a candidate target, and treatment of fibronectin with recombinant HtrA1 led to the generation of fibronectin-degradation products that may be involved in cartilage catabolism. Consistently, treatment of synovial fibroblasts with HtrA1 or HtrA1-generated fibronectin fragments resulted in the specific induction of matrix metalloprotease 1 and matrix metalloprotease 3 expression, suggesting that HtrA1 contributes to the destruction of extracellular matrix through both direct and indirect mechanisms.Human HtrA1 (L56) is a member of the HtrA 3 (High temperature requirement) family of serine proteases, a well defined group of proteases sharing many of the characteristics associated with bacterial HtrAs (1). Such features include a highly conserved trypsin-like serine protease domain and at least one PDZ domain at the C terminus. In addition, HtrA1 contains an insulin-like growth factor-binding protein domain and a Kazal-type serine protease inhibitor motif at its N terminus (2). Originally identified as a gene down-regulated in SV40-transformed fibroblasts (2), HtrA1 has since been implicated in the modulation of various disease pathologies. Recent reports suggest that HtrA1 plays a protective role in various malignancies because of its tumorsuppressive properties (3-6). Studies have shown that HtrA1 is downregulated in cancerous tissue as compared with normal tissue and that overexpression results in the inhibition of tumor cell growth and proliferation both in vitro and in vivo (5). In contrast to tumor tissue, HtrA1 expression is up-regulated in skeletal muscle of Duchenne muscular dystrophy (7) and in cartilage of osteoarthritic joints (8). Therefore, up-regulation of HtrA1 in osteoarthritic joints may contribute to the development of this debilitating disease.Progressive degradation of components of the extracellular matrix plays an important role in the pathogenesis of arthritic diseases (9, 10). The destruction of the major cartilage components is driven by members of all classes of proteases, including serine proteases, although the matrix metalloproteases (MMPs) are considered to be the primary instigators (11-13). Elevated levels of various MMPs have been identified in the diseased joints of both osteoarthritis (OA) (14 -16) and rheumatoid arthritis (RA) (17) patients, originating primar...

The defining features of the widely conserved HtrA (high temperature requirement) family of serine proteases are the combination of a catalytic protease domain with one or more C-terminal PDZ domains and reversible zymogen activation. Even though HtrAs have previously been implicated in protein quality control and various diseases, including cancer, arthritis, and neuromuscular disorder, the biology of the human family members is not well understood. Our data suggest that HtrA1 is directly involved in the ␤-amyloid pathway as it degrades various fragments of amyloid precursor protein while an HtrA1 inhibitor causes accumulation of A␤ in astrocyte cell culture supernatants. Furthermore, HtrA1 colocalizes with ␤-amyloid deposits in human brain samples. Potential implications in Alzheimer's disease are discussed.protein quality control ͉ amyloid ␤ ͉ C99