Soluble recombinant human thrombomodulin suppresses inflammation-induced gastrointestinal tumor growth in a murine perit
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Soluble recombinant human thrombomodulin suppresses inflammation‑induced gastrointestinal tumor growth in a murine peritonitis model En AMADA1 · Kazumasa Fukuda1 · Koshi Kumagai2 · Hirofumi Kawakubo1 · Yuko Kitagawa1 Received: 18 April 2020 / Accepted: 1 August 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Regulatory T cells (Tregs) and transforming growth factor β (TGF-β) are believed to play key roles in both postoperative pro-inflammatory and anti-inflammatory responses of malignancies. Recombinant human thrombomodulin (rTM) is implied to inhibit the interaction between TGF-β and Tregs. The aim of this study is to evaluate the antitumor effects of rTM against gastrointestinal tumors under systemic inflammation. Mice were subjected to cecal ligation and puncture and percutaneous allogeneic tumor implantation. rTM were introduced by percutaneous injection into the abdominal cavity. The effects of rTM were evaluated by weight of implanted tumor, proportion of Tregs in peripheral blood lymphocytes (PBL) and tumor infiltrating lymphocytes (TIL) and temporal evaluation of serum cytokines. The effect of rTM was also evaluated on the in vitro differentiation of naïve T cells into induced Tregs induced by TGF-β and interleukin (IL) -2. rTM significantly inhibited the proliferation of the implanted tumor cells in an inflammation-dependent manner. rTM also reduced the fractions of regulatory T cells and induced regulatory T cells among both PBL and TIL. Temporal evaluation of serum cytokine levels in the model mice showed that rTM significantly suppressed the increases in the serum levels of IL-2 and TGF-β. An in vitro differentiation assay revealed that rTM inhibited the differentiation of naïve T cells into Tregs triggered by IL-2- and TGF-β. rTM has suppressive effects on inflammation-induced gastrointestinal tumor growth by suggestively affecting differentiation of Tregs. Keywords Thrombomodulin · Anti-tumor immunity · Regulatory T cell · Transforming growth factor beta
Introduction Controlling severe postoperative inflammatory responses due to infectious complications in cancer patients might improve the prognosis [1–4]. Infectious complications trigger synergetic increases in pro-inflammatory and antiinflammatory cytokines [5] likely leads to inactivation of anti-tumor immunity, and transforming growth factor β (TGF-β) and regulatory T cells (Tregs) play key roles in this mechanism [6]. Once a tissue is damaged, TGF-β is released from the extracellular matrix (ECM) where it is activated
* Koshi Kumagai [email protected] 1
Department of Surgery, School of Medicine, Keio University, 35, Shinanomachi, Shinjuku, Tokyo, Japan
Department of Gastroenterological Surgery, The Cancer Institute Hospital of JFCR, 3‑8‑31, Ariake, Koto, Tokyo, Japan
2
[7]. Tregs are a subpopulation of T cells with immunosuppressive potential that play key roles in this response by downregulating the induction and proliferation of effector T cells. Chemokines that were produced by Tregs
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