Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Interferon-γ is a therapeutic target molecule for prevention of postoperative adhesion formation

Nature Medicine volume 14, pages 437–441 (2008)Cite this article

Abstract

Intestinal adhesions are bands of fibrous tissue that connect the loops of the intestine to each other, to other abdominal organs or to the abdominal wall1,2,3. Fibrous tissue formation is regulated by the balance between plasminogen activator inhibitor type 1 (PAI-1) and tissue-type plasminogen activator (tPA), which reciprocally regulate fibrin deposition. Several components of the inflammatory system, including cytokines4, chemokines, cell adhesion molecules and neuropeptide substance P, have been reported to participate in adhesion formation4,5,6,7. We have used cecal cauterization to develop a unique experimental mouse model of intestinal adhesion. Mice developed severe intestinal adhesion after this treatment. Adhesion development depended upon the interferon-γ (IFN-γ) and signal transducer and activator of transcription-1 (STAT1) system. Natural killer T (NKT) cell–deficient mice developed adhesion poorly, whereas they developed severe adhesion after reconstitution with NKT cells from wild-type mice, suggesting that NKT cell IFN-γ production is indispensable for adhesion formation. This response does not depend on STAT4, STAT6, interleukin-12 (IL-12), IL-18, tumor necrosis factor-α, Toll-like receptor 4 or myeloid differentiation factor-88–mediated signals. Wild-type mice increased the ratio of PAI-1 to tPA after cecal cauterization, whereas Ifng−/− or Stat1−/− mice did not, suggesting that IFN-γ has a crucial role in the differential regulation of PAI-1 and tPA. Additionally, hepatocyte growth factor, a potent mitogenic factor for hepatocytes8,9, strongly inhibited intestinal adhesion by diminishing IFN-γ production, providing a potential new way to prevent postoperative adhesions.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: NKT cells are the main contributors to postsurgical adhesion formation.
Figure 2: Rapid IFN-γ production by NKT cells is causative in postsurgical adhesion formation.
Figure 3: HGF inhibits IFN-γ–STAT1–dependent PAI-1 induction and postsurgical adhesion formation.
Figure 4: Causative role of NKT cell IFN-γ production in induction of postsurgical adhesion formation.

Similar content being viewed by others

References

  1. Holmdahl, L. The role of fibrinolysis in adhesion formation. Eur. J. Surg. 163 (Suppl. 577), 24–31 (1997).

    Google Scholar 

  2. Raftery, A.T. Regeneration of peritoneum: a fibrinolytic study. J. Anat. 129, 659–664 (1979).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Sulaiman, H., Dawson, L., Laurent, G.J., Bellingan, G.J. & Herrick, S.E. Role of plasminogen activators in peritoneal adhesion formation. Biochem. Soc. Trans. 30, 126–131 (2002).

    Article  CAS  Google Scholar 

  4. Holmdahl, L. & Ivarsson, M.L. The role of cytokines, coagulation, and fibrinolysis in peritoneal tissue repair. Eur. J. Surg. 165, 1012–1109 (1999).

    Article  CAS  Google Scholar 

  5. Fanciullacci, M., Fedi, S., Alessandri, M. & Pietrini, U. Substance P–induced fibrinolysis in the forearm of healthy humans. Experientia 49, 242–244 (1993).

    Article  CAS  Google Scholar 

  6. Reed, K.L. et al. Neurokinin-1 receptor and substance P messenger RNA levels increase during intraabdominal adhesion formation. J. Surg. Res. 108, 165–172 (2002).

    Article  CAS  Google Scholar 

  7. Reed, K.L. et al. A neurokinin 1 receptor antagonist decreases postoperative peritoneal adhesion formation and increases peritoneal fibrinolytic activity. Proc. Natl. Acad. Sci. USA 101, 9115–9120 (2004).

    Article  CAS  Google Scholar 

  8. Miyazawa, K. et al. Molecular cloning and sequence analysis of cDNA for human hepatocyte growth factor. Biochem. Biophys. Res. Commun. 163, 967–973 (1989).

    Article  CAS  Google Scholar 

  9. Nakamura, T. et al. Molecular cloning and expression of human hepatocyte growth factor. Nature 342, 440–443 (1989).

    Article  CAS  Google Scholar 

  10. Ellis, H. The clinical significance of adhesions: focus on intestinal obstruction. Eur. J. Surg. 163 (Suppl. 577), 5–9 (1997).

    Google Scholar 

  11. Ellis, H. et al. Adhesion-related hospital readmissions after abdominal and pelvic surgery: a retrospective cohort study. Lancet 353, 1476–1480 (1999).

    Article  CAS  Google Scholar 

  12. Menzies, D. & Ellis, H. Intestinal obstruction from adhesions–how big is the problem? Ann. R. Coll. Surg. Engl. 72, 60–63 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Parker, M.C. et al. Colorectal surgery: the risk and burden of adhesion-related complications. Colorectal Dis. 6, 506–511 (2004).

    Article  CAS  Google Scholar 

  14. Ghellai, A.M. et al. Role of transforming growth factor-β1 in peritonitis-induced adhesions. J. Gastrointest. Surg. 4, 316–323 (2000).

    Article  CAS  Google Scholar 

  15. Chung, D.R. et al. CD4+ T cells regulate surgical and postinfectious adhesion formation. J. Exp. Med. 195, 1471–1478 (2002).

    Article  CAS  Google Scholar 

  16. Bendelac, A., Savage, P.B. & Teyton, L. The biology of NKT cells. Annu. Rev. Immunol. 25, 297–336 (2007).

    Article  CAS  Google Scholar 

  17. Taniguchi, M., Harada, M., Kojo, S., Nakayama, T. & Wakao, H. The regulatory role of Vα14 NKT cells in innate and acquired immune response. Annu. Rev. Immunol. 21, 483–513 (2003).

    Article  CAS  Google Scholar 

  18. Yoshimoto, T. & Paul, W.E. CD4pos, NK1.1pos T cells promptly produce interleukin 4 in response to in vivo challenge with anti-CD3. J. Exp. Med. 179, 1285–1295 (1994).

    Article  CAS  Google Scholar 

  19. Cui, J. et al. Requirement for Vα14 NKT cells in IL-12–mediated rejection of tumors. Science 278, 1623–1626 (1997).

    Article  CAS  Google Scholar 

  20. Meraz, M.A. et al. Targeted disruption of the Stat1 gene in mice reveals unexpected physiologic specificity in the JAK-STAT signaling pathway. Cell 84, 431–442 (1996).

    Article  CAS  Google Scholar 

  21. Kawano, T. et al. Natural killer–like nonspecific tumor cell lysis mediated by specific ligand-activated Vα14 NKT cells. Proc. Natl. Acad. Sci. USA 95, 5690–5693 (1998).

    Article  CAS  Google Scholar 

  22. Kaplan, M.H., Sun, Y.L., Hoey, T. & Grusby, M.J. Impaired IL-12 responses and enhanced development of TH2 cells in Stat4-deficient mice. Nature 382, 174–177 (1996).

    Article  CAS  Google Scholar 

  23. Takeda, K. et al. Essential role of Stat6 in IL-4 signalling. Nature 380, 627–630 (1996).

    Article  CAS  Google Scholar 

  24. Katayama, I. & Nishioka, K. Substance P augments fibrogenic cytokine-induced fibroblast proliferation: possible involvement of neuropeptide in tissue fibrosis. J. Dermatol. Sci. 15, 201–206 (1997).

    Article  CAS  Google Scholar 

  25. Zimmer, A. et al. Hypoalgesia in mice with a targeted deletion of the tachykinin 1 gene. Proc. Natl. Acad. Sci. USA 95, 2630–2635 (1998).

    Article  CAS  Google Scholar 

  26. Holmdahl, L., Eriksson, E., al-Jabreen, M. & Risberg, B. Fibrinolysis in human peritoneum during operation. Surgery 119, 701–705 (1996).

    Article  CAS  Google Scholar 

  27. Kuroiwa, T. et al. Hepatocyte growth factor ameliorates acute graft-versus-host disease and promotes hematopoietic function. J. Clin. Invest. 107, 1365–1373 (2001).

    Article  CAS  Google Scholar 

  28. Ido, A., Numata, M., Kodama, M. & Tsubouchi, H. Mucosal repair and growth factors: recombinant human hepatocyte growth factor as an innovative therapy for inflammatory bowel disease. J. Gastroenterol. 40, 925–931 (2005).

    Article  Google Scholar 

  29. Kennedy, R., Costain, D.J., McAlister, V.C. & Lee, T.D. Prevention of experimental postoperative peritoneal adhesions by N,O-carboxymethyl chitosan. Surgery 120, 866–870 (1996).

    Article  CAS  Google Scholar 

  30. Kocak, I., Unlu, C., Akcan, Y. & Yakin, K. Reduction of adhesion formation with cross-linked hyaluronic acid after peritoneal surgery in rats. Fertil. Steril. 72, 873–878 (1999).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This study was supported by a Grant-in-Aid for Scientific Research on Priority Areas and a Hitech Research Center grant from the Ministry of Education, Culture, Sports, Science and Technology of Japan and a Grant-in-Aid for Scientific Research (B; No. 19390342) from the Japan Society for Promotion of Science.

Author information

Author notes

  1. Hisashi Kosaka and Tomohiro Yoshimoto: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Surgery, Hyogo College of Medicine, 1-1, Mukogawa, Nishinomiya, Hyogo, 663-8501, Japan

    Hisashi Kosaka & Jiro Fujimoto

  2. Department of Immunology and Medical Zoology, Hyogo College of Medicine, 1-1, Mukogawa, Nishinomiya, Hyogo, 663-8501, Japan

    Tomohiro Yoshimoto & Kenji Nakanishi

  3. Core Research for Evolutional Science and Technology, Japan Science and Technology Corporation, 4-1-8, Honmachi, Kawaguchi, Saitama, 332-0012, Japan

    Tomohiro Yoshimoto & Kenji Nakanishi

  4. Intractable Immune System Disease Research Center, Tokyo Medical University, 6-1-1, Shinjuku, Shinjuku-ku, Tokyo, 160-8402, Japan

    Takayuki Yoshimoto

Authors
  1. Hisashi Kosaka
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tomohiro Yoshimoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Takayuki Yoshimoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jiro Fujimoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kenji Nakanishi
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Tomohiro Yoshimoto and K.N. formulated the hypothesis and initiated and organized the study; H.K. and Tomohiro Yoshimoto performed the main experimental work and analyzed the data; Takayuki Yoshimoto helped with some experimental procedures; Tomohiro Yoshimoto and K.N. oversaw the experiments, analyzed the data and provided the main funding for the research; J.F. contributed to data discussion; Tomohiro Yoshimoto drafted the manuscript and K.N. prepared the final manuscript.

Corresponding author

Correspondence to Kenji Nakanishi.

Supplementary information

Supplementary Text and Figures

Supplementary Figs. 1–3, Supplementary Tables 1 and 2, and Supplementary Methods (PDF 301 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kosaka, H., Yoshimoto, T., Yoshimoto, T. et al. Interferon-γ is a therapeutic target molecule for prevention of postoperative adhesion formation. Nat Med 14, 437–441 (2008). https://doi.org/10.1038/nm1733

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm1733

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing