Transforming growth factor beta 1 (TGF-beta 1) induced neutrophil recruitment to synovial tissues: implications for TGF-beta-driven synovial inflammation and hyperplasia.

Abstract

We have studied the consequences of introducing human recombinant transforming growth factor beta 1 (hrTGF-beta 1) into synovial tissue of the rat, to begin to better understand the significance of the fact that biologically active TGF-beta is found in human arthritic synovial effusions. Within 4-6 h after the intra-articular injection of 1 microgram of hrTGF-beta 1 into rat knee joints, extensive recruitment of polymorphonuclear leukocytes (PMNs) was observed. Cytochemistry and high resolution histological techniques were used to quantitate the influx of PMNs, which peaked 6 h post-injection. In a Boyden chamber assay, hrTGF-beta 1 at 1-10 fg/ml elicited a chemotactic response from PMNs greater in magnitude than that evoked by FMLP, establishing that TGF-beta 1 is an effective chemotactic agent for PMNs in vitro as well as in vivo. That PMNs may represent an important source of TGF-beta in inflammatory infiltrates was strongly suggested by a demonstration that stored TGF-beta 1 was secreted during phorbol myristate acetate-stimulated degranulation in vitro. Acid/ethanol extracts of human PMNs assayed by ELISA contained an average of 355 ng of TGF/beta 1 per 10(9) cells potentially available for secretion during degranulation of PMNs. [3H]Thymidine incorporation in vivo and autoradiography of tissue sections revealed that widespread cell proliferation was triggered by TGF-beta 1 injection. Synovial lining cells and cells located deep within the subsynovial connective tissue were identified as sources of at least some of the new cells that contribute to TGF-beta 1-induced hyperplasia. Our results demonstrate that TGF-beta is capable of exerting pathogenic effects on synovial tissue and that PMNs may represent a significant source of the TGF-beta present in synovial effusions.

The Multifaceted Roles Neutrophils Play in the Tumor Microenvironment

“…TGFβ was also shown to prevent the production of ROS, reactive nitrogen intermediates and IL-1β by neutrophils [86]. Furthermore, TGFβ has even been shown to be a potent chemoattractant for neutrophils taking a central part in their recruitment to sites of inflammation [87][88][89]. However, another study showed that TGFβ reduces the expression of the adhesion molecule L-Selectin, resulting in impaired neutrophil recruitment to sites of inflammation [86].…”

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

“…This subset of innate immune cells has important functions in infection and inflammation, and includes neutrophils, eosinophils, and basophils. TGF-b induces chemotaxis of both neutrophils (Brandes et al 1991;Fava et al 1991;Reibman et al 1991) and eosinophils (Luttmann et al 1998). At the molecular level, Smad3 may be required for TGFb-induced neutrophil migration, as Smad3 2/2 neutrophils show impaired chemotactic responses (Yang et al 1999).…”

Role of cytokines in experimental arthritis

“…Thus the effects of TGF-/3 in animal models are conflicting, with evidence to suggest both a contributory and inhibitory role in the pathogenic events. Thus, if injected locally into rat synovial joints, TGF-/3 causes a rapid leucocyte infiltration, with hyperplasia leading to synovitis [34,35]. In contrast, if injected systemically, TGF-^S was found to antagonize the development of polyarthritis in susceptible rats and prevent the induction of CIA in DBA/1 mice [36,37], The inhibitory effect observed with systemic administration may be through limitation of migration of inflammatory cells into the joint.…”