Transforming growth factor beta 1, a potent chemoattractant for human neutrophils, bypasses classic signal-transduction pathways.

Abstract

Transforming growth factor .1 (TGF-fl1), a homodimeric polypeptide (Mr 25,000), derives from inflammatory cells and acts as a chemoattractant for monocytes and fibroblasts. We report here that TGF-131 is also the most potent chemoattractant yet described for human peripheral blood neutrophils. Recombinant TGF-,t1 elicited dose-dependent directed migration of neutrophils under agarose that was inhibited in the presence of a neutalizing antibody to TGF-j91.Maximal chemotaxis was evoked by TGF-181 at femtomolar concentrations, whereas conventional chemoattractants act at nanomolar concentrations: on a molar basis, TGF-.81 was 150,000 times more potent than fMet-Leu-Phe. In contrast, TGF-,1 provoked neither exocytosis nor the production of superoxide by neutrophils. We further analyzed the mechanism by which TGF-p1 elicits chemotaxis (GTPase activity, Transforming growth factor /31 (TGF-,B1), a homodimeric polypeptide (Mr 25,000) originally purified from human platelets and placenta and from bovine kidney, may also be derived from inflammatory cells (macrophages, T lymphocytes, and neutrophils) (1, 2). TGF-f31 is a member of a multigene family and, although initially defined by its ability to stimulate anchorage-independent growth of nonneoplastic rat kidney fibroblasts (3), it demonstrates a wide variety of effects. TGF-pB1 elicits chemotaxis offibroblasts in concert with the synthesis of matrix proteins (collagen, fibronectin) (4,5) and is also a chemoattractant for peripheral blood monocytes at femtomolar concentrations (6).Neutrophils are the initial cell type found at areas of tissue damage. After exposure to phlogistons such as complement components or bacterial chemoattractants, neutrophils adhere to vascular surfaces, undergo chemotaxis, degranulate, and generate toxic oxygen metabolites (7). Since latent TGF-,31 may be activated by the low pH at inflammatory sites or by tissue proteases or exoproteases found on inflammatory cells, we investigated whether TGF-1B1 might in turn trigger neutrophil functions. We compared the effects of TGF-P1 with those of fMet-Leu-Phe (fMLP) on the recruitment (chemotaxis) and activation (degranulation and superoxide generation) of neutrophils. TGF-,j1 was an exquisitely potent chemoattractant, yet selective in eliciting only chemotaxis by neutrophils. Moreover, TGF-f31 bypassed classic signaling mechanisms (GTPase activity, intracellular Ca2+, actin polymerization) for chemotaxis and triggered protein synthesis. MATERIALS AND METHODSMaterials. Hepes-buffered saline (150 mM Na+/1.2 mM Mg2+/1.3 mM Ca2+/155 mM Cl-/10 mM Hepes, pH 7.43) or phosphate-buffered saline with Ca2+ and Mg2+ (0.68 mM Ca2+/0.5 mM Mg2+, pH 7.43) was used for all cell suspensions. fMLP was stored at 10 mg/ml in dimethyl sulfoxide and diluted into buffer before use. Ficoll 400, horse ferricytochrome c, and bovine serum albumin were obtained from Sigma. [_y-32P]GTP was purchased from Amersham. Recombinant human TGF-,81 and partially purified goat antibody to TGF-,81 were gifts of Michael Palladino (Ge...

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