Increased Soluble CD4 in Serum of Rheumatoid Arthritis Patients Is Generated by Matrix Metalloproteinase (MMP)-Like Proteinases

Abstract

Higher soluble CD4 (sCD4) levels in serum have been detected in patients of infectious and chronic inflammatory diseases. However, how and why sCD4 is produced remains poorly understood. We establish sensitive ELISA and WB assays for sCD4 detection in conditioned medium of in vitro cell culture system and serum of chronic inflammatory patients. Serum samples from patients with systemic lupus erythematosus (SLE) (n = 79), rheumatoid arthritis (RA) (n = 59), ankylosing spondylitis (AS) (n = 25), gout (n = 31), and normal controls (n = 99) were analyzed using ELISA for sCD4 detection. Results from each assay were analyzed by the Kruskal-Wallis test. Dunn’s multiple comparison post-test was then applied between groups. We confirm that cells expressing exogenous CD4 produce sCD4 in a constitutive and PMA-induced manner. Importantly, sCD4 production in a heterologous expression system is inhibited by GM6001 and TAPI-0, suggesting receptor shedding by matrix metalloproteinase (MMP)-like proteinases. Moreover, similar findings are recapitulated in human primary CD4+ T cells. Finally, we show that serum sCD4 levels are increased in patients of chronic inflammatory diseases including RA and SLE, but not in those with gout. Intriguingly, sCD4 levels in RA patients are correlated positively with the disease activities and higher sCD4 levels seem to associate with poor prognosis. Taken together, we conclude that CD4 is shed from cell surface by a MMP-like sheddase and sCD4 level is closely related with the inflammatory condition in certain chronic diseases. Hence, sCD4 might be considered an important parameter for RA disease progression with potential diagnostic importance.

Retraction: Polyphosphate-induced matrix metalloproteinase-3-mediated proliferation in rat dental pulp fibroblast-like cells is mediated by a Wnt5 signaling cascade

“…MMP-3 has been implicated in joint and soft tissue destruction associated with these conditions, where it participates in the inflammatory response (10)(11)(12)(13). Synthesis of MMP-3 is tightly controlled in vivo (12,14).…”

Retraction: Products of dentin matrix protein-1 degradation by interleukin-1β-induced matrix metalloproteinase-3 promote proliferation of odontoblastic cells

“…Because matrix metalloproteinases (MMPs) are able to process virtually any component of the extracellular matrix (ECM), including collagen, laminin, and bioactive molecules, it has been suggested that MMPs may be important in inflammatory conditions, such as rheumatoid arthritis, metastasis and periodontitis (1,2). In particular, MMP-3 (known as stromelysin-1) has a wide substrate specificity and is capable of degrading many types of ECM proteins, such as collagen types II, III, IV, IX, and X, proteoglycans, fibronectin, laminin, and elastin (1,2), rendering MMP-3 crucial in connective tissue and bone remodeling (3,4).…”

“…In particular, MMP-3 (known as stromelysin-1) has a wide substrate specificity and is capable of degrading many types of ECM proteins, such as collagen types II, III, IV, IX, and X, proteoglycans, fibronectin, laminin, and elastin (1,2), rendering MMP-3 crucial in connective tissue and bone remodeling (3,4). However, while it is intuitive that dental pulp destruction may be a function of MMPs, our previous study reported that MMP-3 actually accelerates wound healing following dental pulp injury (5,6).…”

Retraction：Polyphosphate-induced matrix metalloproteinase-3-mediated differentiation in rat dental pulp fibroblast-like cells

“…MMP-3 has been implicated in the joint and soft-tissue destruction associated with these conditions, where it participates in the inflammatory response (10)(11)(12)(13)(14). MMP-3 synthesis is tightly controlled in vivo (13,15).…”