Pre–B cell colony‐enhancing factor/visfatin, a new marker of inflammation in rheumatoid arthritis with proinflammatory and matrix‐degrading activities

Abstract

Objective. To study possible mechanisms that mediate induction of the recently described adipocytokine pre-B cell colony-enhancing factor (PBEF) in joints of patients with rheumatoid arthritis (RA), and to analyze whether levels of PBEF correlate with disease severity and whether PBEF itself has the potential to act as a proinflammatory and destructive mediator in RA.Methods. RA synovial fibroblasts (RASFs) and monocytes were stimulated with Toll-like receptor (TLR) ligands, cytokines, and recombinant human PBEF or were transfected with PBEF expression constructs or with PBEF-specific small interfering RNA. Production of interleukin-6 (IL-6), IL-8, and tumor necrosis factor ␣ (TNF␣) was measured by enzymelinked immunosorbent assay, and expression of matrix metalloproteinases (MMPs) was assessed by real-time polymerase chain reaction. PBEF expression in synovial tissue, synovial fluid, serum, and SFs was assessed by immunohistochemistry, in situ hybridization, Western blotting, and enzyme immunoassays. Results. In RASFs, PBEF was up-regulated by

Suppression of leukocyte infiltration and cartilage degradation by selective inhibition of pre-B cell colony-enhancing factor/visfatin/nicotinamide phosphoribosyltransferase: Apo866-mediated therapy in human fibroblasts and murine collagen-induced arthrit

“…PBEF is detectable in serum and synovial fluid (1,6), and the levels of PBEF have been found to be increased in patients with rheumatoid arthritis, in whom it is clinically correlated with the Disease Activity Score in 28 joints and elevated C-reactive protein level (1,2,6). Other groups have detected PBEF in a variety of bodily fluids (35,(38)(39)(40)(41), and the levels appear to be correlated with inflammation (35,39,40).…”

“…Several groups have shown that PBEF interacts with the insulin receptor (8-10); however, this notion remains controversial (11,12), and it may be that PBEF signals through an alternative signaling route. It is also unlikely that this signaling effect is attributable to the endotoxin that may be present in PBEF preparations, since coincubation with polymixin B shows no abrogation of PBEF signaling (6,10,13).In vitro activation of signaling pathways by PBEF has been shown to regulate the expression of metalloproteinases, chemokines, and cytokines (6,7,(9)(10)(11)(12), but the in vivo contribution of this mediator of arthritis progression remains unclear. The recently developed small molecule inhibitor APO866 has been shown to act as a competitive inhibitor of PBEF/NAMPT activity by inhibiting binding of its natural substrate, nicotinamide (14,15).…”

“…processes via activation of transcriptional events through NF-B, phosphatidylinositol 3-kinase, and MAP kinase (6)(7)(8). Several groups have shown that PBEF interacts with the insulin receptor (8)(9)(10); however, this notion remains controversial (11,12), and it may be that PBEF signals through an alternative signaling route.…”

“…Several groups have shown that PBEF interacts with the insulin receptor (8)(9)(10); however, this notion remains controversial (11,12), and it may be that PBEF signals through an alternative signaling route. It is also unlikely that this signaling effect is attributable to the endotoxin that may be present in PBEF preparations, since coincubation with polymixin B shows no abrogation of PBEF signaling (6,10,13).…”

“…In vitro activation of signaling pathways by PBEF has been shown to regulate the expression of metalloproteinases, chemokines, and cytokines (6,7,(9)(10)(11)(12), but the in vivo contribution of this mediator of arthritis progression remains unclear. The recently developed small molecule inhibitor APO866 has been shown to act as a competitive inhibitor of PBEF/NAMPT activity by inhibiting binding of its natural substrate, nicotinamide (14,15).…”