Abstract
Postoperative adhesion formation often ruins the quality of life or is an obstacle to illnesses with curative operation such as cancer. Previously we demonstrated that interferon-γ-promoted fibrin deposition drove postoperative adhesion formation. However, its underlying cellular and molecular mechanisms remain poorly understood. We found that myofibroblasts of the adhesion predominantly expressed signature molecules of mesothelial cells that line the serosa. Microarray analysis revealed IL-6 as a key underlying player, supported by elevated IL-6 levels in the peritoneal fluid of post-laparotomy human subjects. Injured serosa of cecum-cauterized mice also exhibited induction of Il6, which was followed by Tnf, concomitant with rapid accumulation of neutrophils, substantial population of which expressed TGF-β1, a master regulator of fibrosis. Besides, neutrophil-ablated mice showed reduction in induction of the adhesion, suggesting that TGF-β1+neutrophils triggered the adhesion. Human neutrophils expressed TGFB1 in response to TNF-α and TNF in response to IL-6. Moreover, anti-IL-6 receptor monoclonal antibody abrogated neutrophil recruitment and adhesion formation. Thus, IL-6 signaling represents a potential target for the prevention of postoperative adhesions.
Highlights
Postoperative adhesion formation often ruins the quality of life or is an obstacle to illnesses with curative operation such as cancer
On day 3, αSMA+ myofibroblasts, likely of mesothelial cell origin (Fig. 1), produced similar levels of TGF-β1 (Fig. 3f). These results suggested that neutrophils migrating to the injured serosa likely produce TGF-β1, thereby inducing collagen production by mesothelial cell-derived myofibroblasts and promoting adhesion formation
interleukin 6 (IL-6) by itself could not induce TGFB1 in either neutrophils or mesothelial cells (Fig. 4), IL-6 activated the expression of CXCL2 and TNF in mesothelial cells and neutrophil, respectively. The former IL-6-induced CXCL2 might be involved in the accumulation of neutrophils, and the latter IL-6-induced TNF might contribute to TGF-β1 production in neutrophils. These results suggest that the crosstalk between mesothelial cells and neutrophils might induce early TGF-β1 in neutrohils, which initiates the differentiation of mesothelial cells into myofibroblasts, an essential step for adhesion formation
Summary
Postoperative adhesion formation often ruins the quality of life or is an obstacle to illnesses with curative operation such as cancer. We previously reported that levels of the plasminogen activator inhibitor type 1 (PAI-1), a potent inhibitor of fibrinolysis[6], were increased in injured ceca and remnant liver in a manner dependent on interferon gamma (IFN-γ) following cecal cauterization and partial hepatectomy, respectively. This increase was required for the development of postsurgical adhesions[7,8]. We investigated mesothelial cells as a source of collagen production in postoperative adhesions, explored molecular mechanisms of adhesion using microarray analysis, and identified interleukin 6 (IL-6) signaling as a novel therapeutic target for preventing postoperative adhesion formation
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