TRANSFORMING GROWTH FACTOR-BETA-1, A POTENT CHEMOATTRACTANT FOR HUMAN NEUTROPHILS, BYPASSES CLASSIC SIGNAL-TRANSDUCTION PATHWAYS

Transforming growth factor-beta-1 (TGF-beta-1), a homodimeric polypeptide (M(r) 25,000), derives from inflammatory cells and acts as a chemoattractant for monocytes and fibroblasts. We report here that TGF-beta-1 is also the most potent chemoattractant yet described for human peripheral blood neutrophils. Recombinant TGF-beta-1 elicited dose-dependent directed migration of neutrophils under agarose that was inhibited in the presence of a neutralizing antibody to TGF-beta-1. Maximal chemotaxis was evoked by TGF-beta-1 at femtomolar concentrations, whereas conventional chemoattractants act at nanomolar concentrations: on a molar basis, TGF-beta-1 was 150,000 times more potent than fMet-Leu-Phe. In contrast, TGF-beta-1 provoked neither exocytosis nor the production of superoxide by neutrophils. We further analyzed the mechanism by which TGF-beta-1 elicits chemotaxis (GTPase activity, [Ca2+], and actin polymerization). In contrast to the conventional chemoattractant fMet-Leu-Phe, TGF-beta neither activated classic heterotrimeric guanine nucleotide-binding proteins nor provoked global mobilization of intracellular Ca2+. Chemoattraction by both fMet-Leu-Phe and TGF-beta-1 was inhibited by cycloheximide and actinomycin D. Moreover, chemotaxis in response to TGF-beta-1 was associated with the polymerization of actin. The selectivity and potency of TGF-beta-1 as a chemoattractant suggest that it elicits directed cell migration by means of a pathway that depends not on classic intracellular signals but on protein synthesis.