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 (Mr 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.
Reibman
J
J
Division of Pulmonary Medicine, New York University Medical Center, NY 10016.
Meixler
S
S
Lee
T C
TC
Gold
L I
LI
Cronstein
B N
BN
Haines
K A
KA
Kolasinski
S L
SL
Weissmann
G
G
D002118:Calcium / Q000097:blood; D002462:Cell Membrane / Q000201:enzymology; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D003600:Cytosol / Q000378:metabolism; D020558:GTP Phosphohydrolases / Q000097:blood; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology*; D015398:Signal Transduction; D013481:Superoxides / Q000097:blood; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
D016212:Transforming Growth Factor beta; D013481:Superoxides; D009240:N-Formylmethionine Leucyl-Phenylalanine; D020558:GTP Phosphohydrolases; D002118:Calcium