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

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.

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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.

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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.

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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.

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

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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

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