Download PDF
Thromb Haemost 2004; 91(06): 1194-1201
DOI: 10.1160/TH03-09-0595
Wound Healing and Inflammation/Infection
Schattauer GmbH

Protective role of interleukin-6 in coagulatory and hemostatic disturbance induced by lipopolysaccharide in mice

Ken-ichiro Inoue
1   Inhalation Toxicology Research Team
2   Pathophysiology Research Team, National Institute for Environmental Studies,Tsukuba, Ibaraki
,
Hirohisa Takano
1   Inhalation Toxicology Research Team
3   Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto
,
Rie Yanagisawa
1   Inhalation Toxicology Research Team
2   Pathophysiology Research Team, National Institute for Environmental Studies,Tsukuba, Ibaraki
,
Miho Sakurai
1   Inhalation Toxicology Research Team
2   Pathophysiology Research Team, National Institute for Environmental Studies,Tsukuba, Ibaraki
,
Akinori Shimada
4   Department of Vaterinary Pathology, Faculty of Agriculture,Tottori University,Tottori
,
Takehito Morita
4   Department of Vaterinary Pathology, Faculty of Agriculture,Tottori University,Tottori
,
Masahiko Sato
5   Department of Hygienics, Gifu Pharmaceutical University, Gifu
,
Shin Yoshino
6   Department of Pharmacology, Kobe Pharmaceutical University, Kobe
,
Toshikazu Yoshikawa
3   Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto
,
Chiharu Tohyama
7   Environmental Health Science Division, National Institute for Environmental Studies,Tsukuba, Ibaraki, Japan
› Author Affiliations
Further Information

Publication History

Received 24 September 2003

Accepted after resubmission 12 February 2004

Publication Date:
02 December 2017 (online)

Also available at
    Permissions and Reprints

Summary

Although the role of interleukin (IL)-6 in inflammatory diseases has been previously examined, its role in hemostasis, fibrinolysis, and coagulation during inflammation remains to be established. The present study elucidated the role of IL-6 in hemostatic and coagulatory changes during severe inflammation induced by intraperitoneal administration of lipopolysaccharide (LPS: 1 mg/kg) using IL-6 null (-/-) mice. After LPS challenge, IL-6 (-/-) mice revealed significant prolongation of prothrombin time and activated partial thromboplastin time and a significant decrease in platelet counts as compared with wild type mice. LPS treatment induced marked pulmonary hemorrhage with neutrophilic inflammation in IL-6 (-/-) mice, in contrast, only mild neutrophilic infiltration in WT mice confirmed by macroscopic and histological findings.The protein levels of proinflammatory mediators, such as IL-1?, macrophage inflammatory protein (MIP)-1a., MIP-2, macrophage chemoattractant protein1, granulocyte/macrophage-colony-stimulating factor, and keratinocyte chemoattractant in the lungs were significantly greater in IL-6 (-/-) mice than in WT mice after LPS challenge. These results directly indicate that IL-6 is protective against coagulatory and hemostatic disturbance and subsequent pulmonary hemorrhage induced by bacterial endotoxin, at least partly, via the modulation of proinflammatory processes.

Keywords

Interleukin-6 - hemostatic and coagulatory change - lipopolysaccharide - cytokine
 

  • References

  • 1 Le JM, Vilcek J. Interleukin 6: a multifunctional cytokine regulating immune reactions and the acute phase protein response. Lab Invest 1989; 61: 588-602.
    PubMedGoogle Scholar
  • 2 Alonzi T, Fattori E, Cappelletti M. et al. Impaired Stat3 activation following localized inflammatory stimulus in IL-6-deficient mice. Cytokine 1998; 10: 13-8.
    CrossrefPubMedGoogle Scholar
  • 3 Romano M, Sironi M, Toniatti C. et al. Role of IL-6 and its soluble receptor in induction of chemokines and leukocyte recruitment. Immunity 1997; 06: 315-25.
    CrossrefPubMedGoogle Scholar
  • 4 Cuzzocrea S, Sautebin L, De Sarro G. et al. Role of IL-6 in the pleurisy and lung injury caused by carrageenan. J Immunol 1999; 163: 5094-104.
    PubMedGoogle Scholar
  • 5 Alonzi T, Fattori E, Lazzaro D. et al. Interleukin 6 is required for the development of collagen-induced arthritis. J Exp Med 1998; 187: 461-8.
    CrossrefPubMedGoogle Scholar
  • 6 van der Poll T, Levi M, Hack CE. et al. Elimination of interleukin 6 attenuates coagulation activation in experimental endotoxemia in chimpanzees. J Exp Med 1994; 179: 1253-9.
    CrossrefPubMedGoogle Scholar
  • 7 Cuzzocrea S, Mazzon E, Dugo L. et al. Absence of endogenous interleukin-6 enhances the inflammatory response during acute pancreatitis induced by cerulein in mice. Cytokine 2002; 18: 274-85.
    CrossrefPubMedGoogle Scholar
  • 8 Balto K, Sasaki H, Stashenko P. Interleukin-6 deficiency increases inflammatory bone destruction. Infect Immun 2001; 69: 744-50.
    CrossrefPubMedGoogle Scholar
  • 9 Xing Z, Gauldie J, Cox G. et al. IL-6 is an antiinflammatory cytokine required for controlling local or systemic acute inflammatory responses. J Clin Invest 1998; 101: 311-20.
    CrossrefPubMedGoogle Scholar
  • 10 Xing Z, Jordana M, Kirpalani H. et al. Cytokine expression by neutrophils and macrophages in vivo: endotoxin induces tumor necrosis factor-alpha, macrophage inflammatory protein-2, interleukin-1 beta, and interleukin-6 but not RANTES or transforming growth factor-beta 1 mRNA expression in acute lung inflammation. Am J Respir Cell Mol Biol 1994; 10: 148-53.
    CrossrefPubMedGoogle Scholar
  • 11 Crestani B, Cornillet P, Dehoux M. et al. Alveolar type II epithelial cells produce interleukin-6 in vitro and in vivo Regulation by alveolar macrophage secretory products. J Clin Invest 1994; 94: 731-40.
    CrossrefPubMedGoogle Scholar
  • 12 Gando S, Kameue T, Nanzaki S. et al. Cytokines, soluble thrombomodulin and disseminated intravascular coagulation in patients with systemic inflammatory response syndrome. Thromb Res 1995; 80: 519-26.
    CrossrefPubMedGoogle Scholar
  • 13 Morrison DC, Kline LF. Activation of the classical and properdin pathways of complement by bacterial lipopolysaccharides (LPS). J Immunol 1977; 118: 362-8.
    PubMedGoogle Scholar
  • 14 Fourrier F, Chopin C, Goudemand J. et al. Septic shock, multiple organ failure, and disseminated intravascular coagulation Compared patterns of antithrombin III, protein C, and protein S deficiencies. Chest 1992; 101: 816-23.
    CrossrefPubMedGoogle Scholar
  • 15 Kerr R, Stirling D, Ludlam CA. Interleukin 6 and haemostasis. Br J Haematol 2001; 115: 3-12.
    CrossrefPubMedGoogle Scholar
  • 16 Takano H, Yoshikawa T, Ichinose T. et al. Diesel exhaust particles enhance antigeninduced airway inflammation and local cytokine expression in mice. Am J Respir Crit Care Med 1997; 156: 36-42.
    CrossrefPubMedGoogle Scholar
  • 17 Takano H, Yanagisawa R, Ichinose T. et al. Diesel exhaust particles enhance lung injury related to bacterial endotoxin through expression of proinflammatory cytokines, chemokines, and intercellular adhesion molecule-1. Am J Respir Crit Care Med 2002; 165: 1329-35.
    CrossrefPubMedGoogle Scholar
  • 18 Yanagisawa R, Takano H, Inoue K. et al. Enhancement of acute lung injury related to bacterial endotoxin by components of diesel exhaust particles. Thorax 2003; 58: 605-12.
    CrossrefPubMedGoogle Scholar
  • 19 Amrani DL. Regulation of fibrinogen biosynthesis: glucocorticoid and interleukin-6 control. Blood Coagul Fibrinolysis 1990; 01: 443-6.
    CrossrefPubMedGoogle Scholar
  • 20 Stirling D, Hannant WA, Ludlam CA. Transcriptional activation of the factor VIII gene in liver cell lines by interleukin-6. Thromb Haemost 1998; 79: 74-8.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 21 Neumann FJ, Ott I, Marx N. et al. Effect of human recombinant interleukin-6 and interleukin-8 on monocyte procoagulant activity. Arterioscler Thromb Vasc Biol 1997; 17: 3399-405.
    CrossrefPubMedGoogle Scholar
  • 22 Burstein SA, Peng J, Friese P. et al. Cytokineinduced alteration of platelet and hemostatic function. Stem Cells 1996; 14: 154-62.
    CrossrefPubMedGoogle Scholar
  • 23 Strassmann G, Fong M, Windsor S. et al. The role of interleukin-6 in lipopolysaccharideinduced weight loss, hypoglycemia and fibrinogen production, in vivo. Cytokine 1993; 05: 285-90.
    CrossrefPubMedGoogle Scholar
  • 24 Otto JM, Grenett HE, Fuller GM. The coordinated regulation of fibrinogen gene transcription by hepatocyte-stimulating factor and dexamethasone. J Cell Biol 1987; 105: 1067-72.
    CrossrefPubMedGoogle Scholar
  • 25 Zhang Z, Fuentes NL, Fuller GM. Characterization of the IL-6 responsive elements in the gamma fibrinogen gene promoter. J Biol Chem 1995; 270: 24287-91.
    CrossrefPubMedGoogle Scholar
  • 26 Welbourn CR, Young Y. Endotoxin, septic shock and acute lung injury: neutrophils, macrophages and inflammatory mediators. Br J Surg 1992; 79: 998-1003.
    CrossrefPubMedGoogle Scholar
  • 27 Akira S, Hirano T, Taga T. et al. Biology of multifunctional cytokines: IL 6 and related molecules (IL 1 and TNF). Faseb J 1990; 04: 2860-7.
    CrossrefPubMedGoogle Scholar
  • 28 Elias JA, Lentz V. IL-1 and tumor necrosis factor synergistically stimulate fibroblast IL-6 production and stabilize IL-6 messenger RNA. J Immunol 1990; 145: 161-6.
    PubMedGoogle Scholar
  • 29 May LT, Torcia G, Cozzolino F. et al. Interleukin-6 gene expression in human endothelial cells: RNA start sites, multiple IL-6 proteins and inhibition of proliferation. Biochem Biophys Res Commun 1989; 159: 991-8.
    CrossrefPubMedGoogle Scholar
  • 30 Krueger J, Ray A, Tamm I. et al. Expression and function of interleukin-6 in epithelial cells. J Cell Biochem 1991; 45: 327-34.
    CrossrefPubMedGoogle Scholar
  • 31 Zhou D, Munster A, Winchurch RA. Pathologic concentrations of interleukin 6 inhibit T cell responses via induction of activation of TGF-beta. Faseb J 1991; 05: 2582-5.
    CrossrefPubMedGoogle Scholar
  • 32 Calkins CM, Heimbach JK, Bensard DD. et al. TNF receptor I mediates chemokine production and neutrophil accumulation in the lung following systemic lipopolysaccharide. J Surg Res 2001; 101: 232-7.
    CrossrefPubMedGoogle Scholar
  • 33 Baumann H, Gauldie J. The acute phase response. Immunol Today 1994; 15: 74-80.
    CrossrefPubMedGoogle Scholar
  • 34 Riedemann NC, Neff TA, Guo RF. et al. Protective effects of IL-6 blockade in sepsis are linked to reduced C5a receptor expression. J Immunol 2003; 170: 503-7.
    CrossrefPubMedGoogle Scholar
  • 35 Reddy RC, Chen GH, Newstead MW. et al. Alveolar macrophage deactivation in murine septic peritonitis: role of interleukin 10. Infect Immun 2001; 69: 1394-401.
    CrossrefPubMedGoogle Scholar
  • 36 Salez L, Singer M, Balloy V. et al. Lack of IL10 synthesis by murine alveolar macrophages upon lipopolysaccharide exposure Comparison with peritoneal macrophages. J Leukoc Biol 2000; 67: 545-52.
    CrossrefPubMedGoogle Scholar
  • 37 Marchant A, Deviere J, Byl B. et al. Interleukin-10 production during septicaemia. Lancet 1994; 343: 707-8.
    CrossrefPubMedGoogle Scholar
  • 38 van der Poll T, de Waal RMalefyt, Coyle SM. et al. Antiinflammatory cytokine responses during clinical sepsis and experimental endotoxemia: sequential measurements of plasma soluble interleukin (IL)-1 receptor type II, IL-10, and IL-13. J Infect Dis 1997; 175: 118-22.
    CrossrefPubMedGoogle Scholar
  • 39 Heremans H, Dillen C, Groenen M. et al. Role of interferon-gamma and nitric oxide in pulmonary edema and death induced by lipopolysaccharide. Am J Respir Crit Care Med 2000; 161: 110-7.
    CrossrefPubMedGoogle Scholar