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Am J Pathol. Jul 1989; 135(1): 121–133.
PMCID: PMC1880213

Tumor necrosis factor and interferon-gamma induce distinct patterns of endothelial activation and associated leukocyte accumulation in skin of Papio anubis.


Recombinant human interferon (IFN)-gamma (2 X 10(4) or 2 X 10(5) U), tumor necrosis factor (TNF, 10(4) or 10(5) U), or both were injected intracutaneously into baboons (Papio anubis), and biopsies were examined at various intervals for evidence of altered endothelial cell antigen expression, endothelial morphology, and leukocyte infiltration. IFN-gamma induced increased binding of anti-HLA-DP mAb by 24 hours and a mild-to-moderate accumulation of mononuclear cells. TNF induced increased binding of anti-endothelial leukocyte adhesion molecule (ELAM)-1 mAb by 2 hours that was associated with polymorphonuclear leukocyte accumulation, and increased binding of anti-intercellular adhesion molecule (ICAM)-1 mAb by 9 hours that was associated with the onset of progressive mononuclear leukocyte accumulation. TNF also caused endothelial cell hypertrophy and increased vascular permeability. The combination of IFN-gamma and TNF induced a set of changes that qualitatively resemble those of a delayed hypersensitivity reaction to simian agent 8 envelope antigen. These findings are consistent with the concept that cytokine-activated endothelium plays an important role in the adhesion and subsequent extravasation of leukocytes during immune inflammation.

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  • Cotran RS, Gimbrone MA, Jr, Bevilacqua MP, Mendrick DL, Pober JS. Induction and detection of a human endothelial activation antigen in vivo. J Exp Med. 1986 Aug 1;164(2):661–666. [PMC free article] [PubMed]
  • Goerdt S, Zwadlo G, Schlegel R, Hagemeier HH, Sorg C. Characterization and expression kinetics of an endothelial cell activation antigen present in vivo only in acute inflammatory tissues. Exp Cell Biol. 1987;55(3):117–126. [PubMed]
  • Duijvestijn AM, Horst E, Pals ST, Rouse BN, Steere AC, Picker LJ, Meijer CJ, Butcher EC. High endothelial differentiation in human lymphoid and inflammatory tissues defined by monoclonal antibody HECA-452. Am J Pathol. 1988 Jan;130(1):147–155. [PMC free article] [PubMed]
  • Willms-Kretschmer K, Flax MH, Cotran RS. The fine structure of the vascular response in hapten-specific delayed hypersensitivity and contact dermatitis. Lab Invest. 1967 Sep;17(3):334–349. [PubMed]
  • Nightingale G, Hurley JV. Relationship between lymphocyte emigration and vascular endothelium in chronic inflammation. Pathology. 1978 Jan;10(1):27–44. [PubMed]
  • Freemont AJ, Ford WL. Functional and morphological changes in post-capillary venules in relation to lymphocytic infiltration into BCG-induced granulomata in rat skin. J Pathol. 1985 Sep;147(1):1–12. [PubMed]
  • Pober JS. Warner-Lambert/Parke-Davis award lecture. Cytokine-mediated activation of vascular endothelium. Physiology and pathology. Am J Pathol. 1988 Dec;133(3):426–433. [PMC free article] [PubMed]
  • Cotran RS. American Association of Pathologists president's address. New roles for the endothelium in inflammation and immunity. Am J Pathol. 1987 Dec;129(3):407–413. [PMC free article] [PubMed]
  • Montesano R, Orci L, Vassalli P. Human endothelial cell cultures: phenotypic modulation by leukocyte interleukins. J Cell Physiol. 1985 Mar;122(3):424–434. [PubMed]
  • Stolpen AH, Guinan EC, Fiers W, Pober JS. Recombinant tumor necrosis factor and immune interferon act singly and in combination to reorganize human vascular endothelial cell monolayers. Am J Pathol. 1986 Apr;123(1):16–24. [PMC free article] [PubMed]
  • Bevilacqua MP, Pober JS, Wheeler ME, Cotran RS, Gimbrone MA., Jr Interleukin 1 acts on cultured human vascular endothelium to increase the adhesion of polymorphonuclear leukocytes, monocytes, and related leukocyte cell lines. J Clin Invest. 1985 Nov;76(5):2003–2011. [PMC free article] [PubMed]
  • Bevilacqua MP, Pober JS, Mendrick DL, Cotran RS, Gimbrone MA., Jr Identification of an inducible endothelial-leukocyte adhesion molecule. Proc Natl Acad Sci U S A. 1987 Dec;84(24):9238–9242. [PMC free article] [PubMed]
  • Pober JS, Gimbrone MA, Jr, Lapierre LA, Mendrick DL, Fiers W, Rothlein R, Springer TA. Overlapping patterns of activation of human endothelial cells by interleukin 1, tumor necrosis factor, and immune interferon. J Immunol. 1986 Sep 15;137(6):1893–1896. [PubMed]
  • Boyd AW, Wawryk SO, Burns GF, Fecondo JV. Intercellular adhesion molecule 1 (ICAM-1) has a central role in cell-cell contact-mediated immune mechanisms. Proc Natl Acad Sci U S A. 1988 May;85(9):3095–3099. [PMC free article] [PubMed]
  • Dustin ML, Springer TA. Lymphocyte function-associated antigen-1 (LFA-1) interaction with intercellular adhesion molecule-1 (ICAM-1) is one of at least three mechanisms for lymphocyte adhesion to cultured endothelial cells. J Cell Biol. 1988 Jul;107(1):321–331. [PMC free article] [PubMed]
  • Pober JS, Gimbrone MA, Jr, Cotran RS, Reiss CS, Burakoff SJ, Fiers W, Ault KA. Ia expression by vascular endothelium is inducible by activated T cells and by human gamma interferon. J Exp Med. 1983 Apr 1;157(4):1339–1353. [PMC free article] [PubMed]
  • Collins T, Korman AJ, Wake CT, Boss JM, Kappes DJ, Fiers W, Ault KA, Gimbrone MA, Jr, Strominger JL, Pober JS. Immune interferon activates multiple class II major histocompatibility complex genes and the associated invariant chain gene in human endothelial cells and dermal fibroblasts. Proc Natl Acad Sci U S A. 1984 Aug;81(15):4917–4921. [PMC free article] [PubMed]
  • Collins T, Lapierre LA, Fiers W, Strominger JL, Pober JS. Recombinant human tumor necrosis factor increases mRNA levels and surface expression of HLA-A,B antigens in vascular endothelial cells and dermal fibroblasts in vitro. Proc Natl Acad Sci U S A. 1986 Jan;83(2):446–450. [PMC free article] [PubMed]
  • Wedgwood JF, Hatam L, Bonagura VR. Effect of interferon-gamma and tumor necrosis factor on the expression of class I and class II major histocompatibility molecules by cultured human umbilical vein endothelial cells. Cell Immunol. 1988 Jan;111(1):1–9. [PubMed]
  • Lapierre LA, Fiers W, Pober JS. Three distinct classes of regulatory cytokines control endothelial cell MHC antigen expression. Interactions with immune gamma interferon differentiate the effects of tumor necrosis factor and lymphotoxin from those of leukocyte alpha and fibroblast beta interferons. J Exp Med. 1988 Mar 1;167(3):794–804. [PMC free article] [PubMed]
  • Masuyama J, Minato N, Kano S. Mechanisms of lymphocyte adhesion to human vascular endothelial cells in culture. T lymphocyte adhesion to endothelial cells through endothelial HLA-DR antigens induced by gamma interferon. J Clin Invest. 1986 May;77(5):1596–1605. [PMC free article] [PubMed]
  • Dumonde DC, Pulley MS, Paradinas FJ, Southcott BM, O'Connell D, Robinson MR, den Hollander F, Schuurs AH. Histological features of skin reactions to human lymphoid cell line lymphokine in patients with advanced cancer. J Pathol. 1982 Dec;138(4):289–308. [PubMed]
  • Steffen M, Ottmann OG, Moore MA. Simultaneous production of tumor necrosis factor-alpha and lymphotoxin by normal T cells after induction with IL-2 and anti-T3. J Immunol. 1988 Apr 15;140(8):2621–2624. [PubMed]
  • Bianchi AT, Hooijkaas H, Benner R, Tees R, Nordin AA, Schreier MH. Clones of helper T cells mediate antigen-specific, H-2-restricted DTH. Nature. 1981 Mar 5;290(5801):62–63. [PubMed]
  • Katz D, Hilliard JK, Eberle R, Lipper SL. ELISA for detection of group-common and virus-specific antibodies in human and simian sera induced by herpes simplex and related simian viruses. J Virol Methods. 1986 Sep;14(2):99–109. [PubMed]
  • Smith CW, Rothlein R, Hughes BJ, Mariscalco MM, Rudloff HE, Schmalstieg FC, Anderson DC. Recognition of an endothelial determinant for CD 18-dependent human neutrophil adherence and transendothelial migration. J Clin Invest. 1988 Nov;82(5):1746–1756. [PMC free article] [PubMed]
  • Chin W, Hay JB. A comparison of lymphocyte migration through intestinal lymph nodes, subcutaneous lymph nodes, and chronic inflammatory sites of sheep. Gastroenterology. 1980 Dec;79(6):1231–1242. [PubMed]
  • Dvorak HF, Mihm MC, Jr, Dvorak AM, Johnson RA, Manseau EJ, Morgan E, Colvin RB. Morphology of delayed type hypersensitivity reactions in man. I. Quantitative description of the inflammatory response. Lab Invest. 1974 Aug;31(2):111–130. [PubMed]
  • Polverini PJ, Cotran RS, Sholley MM. Endothelial proliferation in the delayed hypersensitivity reaction: an autoradiographic study. J Immunol. 1977 Feb;118(2):529–532. [PubMed]
  • Messadi DV, Pober JS, Fiers W, Gimbrone MA, Jr, Murphy GF. Induction of an activation antigen on postcapillary venular endothelium in human skin organ culture. J Immunol. 1987 Sep 1;139(5):1557–1562. [PubMed]
  • Messadi DV, Pober JS, Murphy GF. Effects of recombinant gamma-interferon on HLA-DR and DQ expression by skin cells in short-term organ culture. Lab Invest. 1988 Jan;58(1):61–67. [PubMed]
  • Bachwich PR, Chensue SW, Larrick JW, Kunkel SL. Tumor necrosis factor stimulates interleukin-1 and prostaglandin E2 production in resting macrophages. Biochem Biophys Res Commun. 1986 Apr 14;136(1):94–101. [PubMed]
  • Gamble JR, Harlan JM, Klebanoff SJ, Vadas MA. Stimulation of the adherence of neutrophils to umbilical vein endothelium by human recombinant tumor necrosis factor. Proc Natl Acad Sci U S A. 1985 Dec;82(24):8667–8671. [PMC free article] [PubMed]
  • Cybulsky MI, Colditz IG, Movat HZ. The role of interleukin-1 in neutrophil leukocyte emigration induced by endotoxin. Am J Pathol. 1986 Sep;124(3):367–372. [PMC free article] [PubMed]
  • Movat HZ, Burrowes CE, Cybulsky MI, Dinarello CA. Acute inflammation and a Shwartzman-like reaction induced by interleukin-1 and tumor necrosis factor. Synergistic action of the cytokines in the induction of inflammation and microvascular injury. Am J Pathol. 1987 Dec;129(3):463–476. [PMC free article] [PubMed]
  • Wankowicz Z, Megyeri P, Issekutz A. Synergy between tumour necrosis factor alpha and interleukin-1 in the induction of polymorphonuclear leukocyte migration during inflammation. J Leukoc Biol. 1988 Apr;43(4):349–356. [PubMed]
  • Rosenbaum JT, Howes EL, Jr, Rubin RM, Samples JR. Ocular inflammatory effects of intravitreally-injected tumor necrosis factor. Am J Pathol. 1988 Oct;133(1):47–53. [PMC free article] [PubMed]
  • Issekutz TB, Stoltz JM, vd Meide P. Lymphocyte recruitment in delayed-type hypersensitivity. The role of IFN-gamma. J Immunol. 1988 May 1;140(9):2989–2993. [PubMed]
  • Kaplan G, Nusrat A, Sarno EN, Job CK, McElrath J, Porto JA, Nathan CF, Cohn ZA. Cellular responses to the intradermal injection of recombinant human gamma-interferon in lepromatous leprosy patients. Am J Pathol. 1987 Aug;128(2):345–353. [PMC free article] [PubMed]
  • Kaplan G, Witmer MD, Nath I, Steinman RM, Laal S, Prasad HK, Sarno EN, Elvers U, Cohn ZA. Influence of delayed immune reactions on human epidermal keratinocytes. Proc Natl Acad Sci U S A. 1986 May;83(10):3469–3473. [PMC free article] [PubMed]

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