TNF 41-62 and TNF 78-96 Have Distinct Effects on LPS-induced Tissue Factor Activity and the Production of Cytokines in Human Blood Cells

Summary

Biological activities of peptides representing two different regions in the TNF molecule were investigated. We have earlier reported that one of the peptides studied, TNF 36-62, induced chemotaxis in granulocytes and monocytes. TNF 41-62, a shorter analog of TNF 36-62, possessed similar chemotactic effects. Both peptides caused a weak enhancement of LPS -induced IL-6 production and tissue factor activity by monocytes in whole blood. The third peptide studied, TNF 78-96, was selected from a region located on the opposite side of the β-sheet sandwich structure of the TNF molecule, and includes the loop 84-88 that has been shown to be involved in TNF receptor interaction. TNF 78-96 possessed properties quite different from TNF 36-62 and TNF 41-62. It amplified several fold PMA-induced secretion of elastase, and enhanced significantly PMA-induced secretion of cathepsin G from the neutrophils, activities which were effectively abolished by an anti-human TNF antibody. The TNF 78-96 peptide also inhibited LPS-induced TF activity in monocytes of whole blood, and it abolished the TNF enhancing effect of LPS-induced TF activty in a dose dependent manner. This suggests that the TNF 78-96 peptide may bind to the TNF receptor(s), without potentiating the same signals as native TNF. It may thereby prevent binding of the native TNF and the resultant activation effect of TNF. It also, at high concentrations, inhibited LPS-induced IL-6 production whereas it caused a doubling of LPS-induced IL-8 in monocytes and granulocytes in whole blood. These results clearly show that distinct TNF activities can be induced by peptide sequences taken from different regions of TNF. The TNF 78-96 peptide might be useful in downregulation of LPS-induced monocyte activations in vivo.

Keywords

Molecular modelling - TNF peptides - leukocytes - tissue factor

• References

• 1 Vasalli P, Grau GE, Piguet PF. TNF in autoimmune diseases, graft-versus-host reaction, and pulmonary fibrosis. Immunol-Ser 1992; 56: 409-30.
• 2 Fiers W. Biologic therapy with TNF: preclinical studies. In Biologic theraphy of cancer: principles and practice. De Vita Jr V, Hellman S, Rosenberg ST. Philadelphia: J. P. Lippincott Company; 1995: 295-327.
• 3 Rothwell NJ, Gridle RF. Metabolic and nutritional effects of TNF. In Tumor necrosis factors. The molecular structures and their emerging role in medicine. Beutler B. New York: Raven Press; 1992: 237-54.
• 4 Tracy KJ. TNF and other cytokines in the metabolism of septic shock and cachexia. Clin Nutr 1992; 11: 1-11.
• 5 Wang JM, Bersani L, Mantovani M. Tumor necrosis factor is chemotactic for monocytes and polymorphonuclear leukocytes. J Immunol 1987; 138: 1469-74.
• 6 Ferrante A, Nandoskar M, Walz A, Goh DHB, Kowanko IC. Effects of tumor necrosis factor alpha and interleukin-1 alpha and beta on human neutrophil migration, respiratory burst and degranulation. Int Arch Allergy Appl Immunol 1988; 86: 82-91.
• 7 Klebanoff SJ, Vadas MA, Harlan JM, Sparks LH, Gamble JR, Agosti JM. Walterdorph Stimulation of neutrophils by tumor necrosis factor. J Immunol 1986; 136: 4220-5.
• 8 Dinarello CA, Cannon JG, Wolff SM. Tumor necrosis factor (cachectin) is an endogenous pyrogen and induces production of interleukin-1. J Exp Med 1986; 163: 1433-50.
• 9 Akira S, Hirano T, Taga T, Kishimoto T. Biology of multifunctional cytokines: IL-6 and related molecules (IL-1 and TNF). FASEB J 1990; 04: 2860-7.
• 10 Smith BW, Gamble RJ, Clark-Lewis I, Vadas MA. Interleukin-8 induces neutrophil transendothelial migration. Immunol 1991; 72: 65-72.
• 11 Halvorsen H, Olsen JO, Østerud B. Granulocytes enhance LPS-induced tissue factor activity in monocytes via an interaction with platelets. J Leukoc Biol 1993; 54: 275-82.
• 12 Rekdal Ø, Konopski Z, Svendsen JS, Winberg JO, Espevik T, Østerud B. The TNF receptors p55 and p75 mediate chemotaxis of PMN induced by TNFa and a TNFa 36-62 peptide. Med Inflamm 1994; 03: 347-52.
• 13 Rekdal Ø, Østerud B, Svendsen JS, Winberg JO. (1996) Evidence for exclusive role of the p55 tumor necrosis factor (TNF) receptor in mediating the TNF-induced collagenase expression by human dermal fibroblasts. J Invest Dermatol 1996; 107: 565-8.
• 14 Eck JE, Sprang RS. The structure of tumor necrosis factor-α at 2.6 Å resolution. J Biol Chem 1989; 264: 17595-605.
• 15 Van Ostade X, Travernier J, Prange T, Fiers W. Localization of the active site of human tumor necrosis factor (hTNF) by mutual analysis. EMBO J 1991; 10: 827-36.
• 16 Bøyum A. Isolation of mononuclear cells and granulocytes from human blood. Scand J Clin Lab Invest 1968; (Suppl) 21: 77-89.
• 17 Engstad CSissener, Lia K, Rekdal Ø, Olsen JO, Østerud B. A novel biological effect of platelet factor 4 (PF4): enhancement of LPS-induced tissue factor activity in monocytes. J Leukoc Biol 1995; 58: 575-81.
• 18 Nacamura K, Powers JC. Mapping the extended substrate binding site of cathepsin G and human leukocyte elastase. Studies with peptide substrates released to the a1-protease inhibitor reactive site. J Biol Chem 1979; 254: 4027-32.
• 19 Østerud B. Platelet activating factor enhancement of lipopolysaccharideinduced tissue factor activity in monocytes: requirement of platelets and granulocytes. J Leukoc Biol 1992; 51: 462-5.
• 20 Tartaglia LA, Goeddel DV. Two TNF receptors. Immunol Today 1992; 13: 151-3.
• 21 Nakamura S, Magesi T, Fukuoka M, Kiati K, Kato A, Watanabe N, Niitsu Y. Interaction between novel tumor necrosis factor-α mutants and receptors on tumor and normal cells. Agric Biol Chem 1991; 55: 53-7.
• 22 Yamagishi JI, Kawashima H, Matsuo N, Ohue M, Yoamayoshi M, Toshikazu F, Kotani H. Mutational analysis of structure-activity relationships in human tumour necrosis factor alpha. Protein Engineering 1990; 03: 713-9.
• 23 van Ginkel CJ, van Aken WG, Oh JI, Vreeken J. Stimulation of monocyte procoagulant activity by adherence to different surfaces. Br J Haematol 1977; 37 (01) 35-45.
• 24 Ternisien C, Ramani M, Ollivier V, Khechai F, Vu T, Hakim J, de Prost D. Endotoxin-induced tissue factor in human monocytes is dependent upon protein kinase C activation. Thromb Haemost 1993; 800-6.
• 25 Brakebusch C, Nophar Y, Kemper O, Engelmann H, Wallach D. Cytoplasmic truncation of the p55 tumour necrosis factor (TNF) receptor abolishes signalling, but not induced shedding of the receptor. EMBO J 1992; 11: 943-50.
• 26 Hale KK, Smith CG, Baker SL, Vanderslice RW, Squires CH, Gleason TM, Tucker KK, Kohno T, Russel DA. Multifunctional regulation of the biological effects of TNF-alpha by the soluble type I and type II TNF receptors. Cytokine 1995; 07: 26-38.
• 27 Rathjen DA, Ferrante A, Aston R. Differential effects of small tumour necrosis factor-α peptides on tumour cell cytotoxicity, neutrophil activation and endothelial cell procoagulant activity. Immunology 1993; 80: 293-9.
• 28 Engelmann H, Holtmann H, Brakebuch C, Avni YS, Sarov I, Nophar Y, Hadas F, Leher O, Wallach D. Antibodies to a soluble form of a tumor necrosis factor (TNF) receptor have TNF-like activity. J Biol Chem 1990; 265: 14497-504.
• 29 Espevik T, Brockhaus M, Loetscher H, Nonstad U, Shalaby R. Characterization of binding and biological effects of monoclonal antibodies against a human tumor necrosis factor. J Exp Med 1990; 171: 415-26.
• 30 Tartaglia LA, Weber RF, Figari IS, Reynolds C, Palladino Jr MA, Goeddel DV. The two different receptors for tumor necrosis factor mediate distinct cellular responces. Proc Natl Acad Sci USA 1991; 88: 9292-6.
• 31 Kumaratilake LM, Rathjen DA, Mack P, Widmer F, Prasertsiriroj V, Ferrante A. A synthetic tumor necrosis factor- agonist peptide enhances human polymorphonuclear leukocyte-mediated killing of Plasmodium falciparum in vitro and suppresses Plasmodium chabaudi infection in mice. J Clin Invest 1995; 95: 2315-23.