Rapid onset synovial inflammation and hyperplasia induced by transforming growth factor beta.

Abstract

Transforming growth factor /3 (TGF (3),t originally isolated from platelets as a 25-kD peptide (1, 2), has been shown to be a product of other inflammatory cells, including lymphocytes (3, 4) and macrophages (5, 6), and to have potent immunomodulatory effects (7). Although five different forms of TGFJ3 have now been characterized (1), only TGF01 and its homologue, TGF02 (8, 9), have thus far been identified in hemopoietic cells (6). Each ofthese peptides has been cloned, demonstrating that TGF01 is encoded as a 390 amino acid precursor (10), TGFs2 as a 412 amino acid precursor (11,12), and that both have a signal peptide of 20-23 amino acids at the NH2 terminus . The processed 112 amino acid chains of the two peptides share 72% sequence homology and appear to bind equally well to TGFS class III receptors (13), although TGFS1 binds with greater affinity than TGF02 to class I and II receptors (14, 15). Interestingly, lymphoid cells appear to possess only class I and II TGF,6 receptors (16), although in vitro, lymphocyte and monocyte responses to TGF01 and 02 appear comparable (6,17,18). The secretion of TGFa peptides by lymphocytes and monocytes only after activation (3-6) implicates these polypeptides in the evolution of immunologic processes, and in recent studies TGFR has been identified in chronic inflammatory tissues (19)(20)(21)(22), including the synovium of rheumatoid arthritis patients (7,22) and in experimentally induced arthritis in rodents (22). To define the role of TGFS in such lesions, we injected natural or recombinant TGF0 directly into the joint cavity of Lewis rats and monitored its effect on cellular recruitment and activation, and on its potential modulation of pathogenic effects. TGF01 and TGF02 were both found to induce synovial erythema, swelling, and leukocyte infiltration . The infiltrating mononuclear cells, activated to express growth factors, likely regulated the pronounced synovial hyperplasia that was apparent within 2-3 d. Based on these observations, it appears that TGF0, released by platelets and inflammatory cells in the arthritic synovium, may directly contribute to the events associated with inflammatory arthropathies.

Regulation of the Immune Response by TGF-β: From Conception to Autoimmunity and Infection

“…The effects of TGF-b on RA development appear to be determined by the anatomical context of cytokine signaling, as local versus systemic modulation of TGF-b activity has opposing effects on disease development in rodent models of RA. For example, injecting TGF-b into the joints of Lewis rats induces synovial inflammation and joint swelling associated with macrophage infiltration and increased expression of IL-1b (Allen et al 1990). Correspondingly, administering a TGF-b blocking antibody into a joint ameliorates group A streptococci -induced arthritis (Wahl et al 1993a).…”

Transforming growth factor-beta (TGF-β) expression and interaction with proteinase 3 (PR3) in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis

“…Studies in patients with rheumatoid arthritis showed local overexpression of bioactive TGF-to be responsible for immunosuppression of activated cells in synovial fluid cells [3]. In animal models of human autoimmune diseases, local or systemic administration of TGF-can modulate onset and course of inflammatory processes [4,5].…”

Neuropeptide Y promotes TGF-β1 production in RAW264.7 cells by activating PI3K pathway via Y1 receptor

“…This in vitro chemoattractant effect has been shown in vivo to affect the recruitment of monocytes to the sites of inflammation, for example intradermal or intraarticular injection of TGF-β1 stimulates monocyte infiltration and matrix deposition [23,24] . Moreover, TGF-β1 mediates monocyte production of cytokines which act as additional mononuclear cell chemoattractants [12,25] .…”