Interstitial collagens I, III, and VI sequester and modulate the multifunctional cytokine oncostatin M.
The binding of certain growth factors and cytokines to components of the extracellular matrix can regulate their local availability and modulate their biological activities. We show that oncostatin M (OSM), a profibrogenic cytokine and modulator of cancer cell proliferation, specifically binds to collagen types I, III, IV, and VI, immobilized on polystyrene or nitrocellulose. Single collagen chains inhibit these interactions in a dose-dependent manner. Cross-inhibition experiments of collagen-derived peptides point to a limited set of OSM-binding collagenous consensus sequences. Furthermore, this interaction is found for OSM but not for other interleukin-6 type cytokines. OSM binding to collagens is saturable, with dissociation constants around 10(-8) m and estimated molar ratios of 1-3 molecules of OSM bound to one molecule of triple helical collagen. Furthermore, collagen-bound OSM is biologically active and able to inhibit proliferation of A375 melanoma cells. We conclude that abundant interstitial collagens dictate the spatial pattern of bioavailable OSM. This interaction could be exploited for devising collagenous peptide-antagonists that modulate OSM bioactivity in tumor growth and fibrotic disorders like rheumatoid arthritis and hepatic fibrosis.
Somasundaram
Rajan
R
Medizinische Klinik I (Gastroenterology/Hepatology), Klinikum Benjamin Franklin, Freie Universität Berlin, Hindenbergdamm 30, 12280 Berlin, Germany.
Ruehl
Martin
M
Schaefer
Benjamin
B
Schmid
Monika
M
Ackermann
Renate
R
Riecken
E O
EO
Zeitz
Martin
M
Schuppan
Detlef
D
D001665:Binding Sites; D001667:Binding, Competitive; D024042:Collagen Type I / Q000737:chemistry / Q000378:metabolism*; D024061:Collagen Type III / Q000737:chemistry / Q000378:metabolism*; D024141:Collagen Type IV / Q000737:chemistry / Q000378:metabolism*; D024142:Collagen Type VI / Q000737:chemistry / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D007457:Iodine Radioisotopes; D007700:Kinetics; D053683:Oncostatin M; D009994:Osmolar Concentration; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D010455:Peptides / Q000378:metabolism*; D011485:Protein Binding; D011489:Protein Denaturation; D017433:Protein Structure, Secondary; D011994:Recombinant Proteins / Q000378:metabolism; D013379:Substrate Specificity
D024042:Collagen Type I; D024061:Collagen Type III; D024141:Collagen Type IV; D024142:Collagen Type VI; D016207:Cytokines; D015850:Interleukin-6; D007457:Iodine Radioisotopes; C508351:OSM protein, human; D010446:Peptide Fragments; D010455:Peptides; D011994:Recombinant Proteins; D053683:Oncostatin M