Transforming growth factor β1 (TGF-β1) induced neutrophil recruitment to synovial tissues: Implications for TGF-β-driven synovial inflammation and hyperplasia

We have studied the consequences of introducing human recombinant transforming growth factor β1 (hrTGF-β1) into synovial tissue of the rat, to begin to better understand the significance of the fact that biologically active TGF-β is found in human arthritic synovial effusions. Within 4-6 h after the intra-articular injection of 1 μg of hrTGF-β1 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-β1 at 1-10 fg/ml elicited a chemotactic response from PMNs greater in magnitude than that evoked by FMLP, establishing that TGF-β1 is an effective chemotactic agent for PMNs in vitro as well as in vivo. That PMNs may represent an important source of TGF-β in inflammatory infiltrates was strongly suggested by a demonstration that stored TGF-β1 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/β1 per 10⁹ 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-β1 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-β1-induced hyperplasia. Our results demonstrate that TGF-β is capable of exerting pathogenic effects on synovial tissue and that PMNs may represent a significant source of the TGF-β present in synovial effusions.