Stimulation of fibroblast chemotaxis by human recombinant tumor necrosis factor alpha (TNF-alpha) and a synthetic TNF-alpha 31-68 peptide.
Macrophages are a major source of fibrogenic factors that promote healing of injured tissue. The recruitment of fibroblasts to sites of tissue injury is a prerequisite for optimal repair of tissue damage. In the present study, human recombinant tumor necrosis factor alpha (hrTNF-alpha), a major macrophage-derived cytokine, was demonstrated to be a potent fibroblast chemoattractant, inducing migration at picomolar concentrations. Anti-hrTNF-alpha monoclonal antibody neutralized most of the fibroblast chemotactic activity generated during short-term culture of human peripheral blood monocytes stimulated with bacterial lipopolysaccharide, suggesting that TNF-alpha is a major monocyte-derived fibroblast chemoattractant. The portion of the human TNF-alpha molecule responsible for its chemotactic stimulation of fibroblasts appears to reside in residues 31-68. This region is highly conserved between TNF-alpha and lymphotoxin. This peptide is not only itself chemotactic but is also able to block the chemotactic response of fibroblasts to hrTNF-alpha and vice versa, suggesting that they each mediate fibroblast migration through similar mechanisms. These data further underscore the potential importance of TNF-alpha in modulating a variety of fibroblast functions, including chemotaxis and synthesis of collagen, glycosaminoglycans, interleukin 1 alpha (IL-1 alpha) and -beta, human histocompatibility leukocyte antigen A and B antigens, collagenase, prostaglandin E2, and IL-6.
Postlethwaite
A E
AE
Division of Connective Tissue Disease, University of Tennessee, Memphis 38163.
Seyer
J M
JM
D000595:Amino Acid Sequence; D000911:Antibodies, Monoclonal; D002478:Cells, Cultured; D002633:Chemotaxis / Q000187:drug effects*; D005347:Fibroblasts / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007231:Infant, Newborn; D007700:Kinetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D008969:Molecular Sequence Data; D009000:Monocytes / Q000187:drug effects / Q000502:physiology; D010446:Peptide Fragments / Q000138:chemical synthesis* / Q000494:pharmacology; D010455:Peptides / Q000138:chemical synthesis* / Q000494:pharmacology; D011994:Recombinant Proteins / Q000494:pharmacology; D012879:Skin Physiological Phenomena; D014409:Tumor Necrosis Factor-alpha / Q000138:chemical synthesis* / Q000276:immunology / Q000494:pharmacology*
D000911:Antibodies, Monoclonal; D008070:Lipopolysaccharides; D010446:Peptide Fragments; D010455:Peptides; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; C066650:tumor necrosis factor alpha (36-68)