Immunosuppressive effects of tacrolimus on macrophages ameliorate experimental colitis

Yoshino, Takayuki; Nakase, Hiroshi; Honzawa, Yusuke; Matsumura, Kayoko; Yamamoto, Shigehiro; Takeda, Yasuhiro; Ueno, S.; Uza, Norimitsu; Masuda, Satohiro; Inui, Ken Ichi; Chiba, Tsutomu

doi:10.1002/ibd.21318

Cited by 64 publications

(66 citation statements)

References 41 publications

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“…It is generally accepted that the therapeutic effects of tacrolimus are a result of its inhibitory actions on T-cell functions, but there is little information concerning the inhibitory effects of tacrolimus on non-immune cells such as colonic myofibroblasts. As an example of the inhibitory actions of tacrolimus on non-T-cell populations, Yoshino et al (48) recently reported the immunosuppressive effects of tacrolimus on macrophages. They demonstrated that the proinflammatory cytokine production from tacrolimus-treated macrophages was significantly lower than that from untreated cells.…”

Section: Discussionmentioning

confidence: 99%

Tacrolimus (FK506) suppresses TNF-α-induced CCL2 (MCP-1) and CXCL10 (IP-10) expression via the inhibition of p38 MAP kinase activation in human colonic myofibroblasts

Aomatsu

Imaeda

Takahashi

et al. 2012

International Journal of Molecular Medicine

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Abstract. In order to investigate the molecular mechanisms underlying the immunosuppressive effects of tacrolimus (FK506) on intestinal inflammation, we examined whether FK506 effects cytokine/chemokine secretion in human colonic myofibroblasts. Human colonic myofibroblasts were isolated from normal human colonic tissue. The mRNA and protein expression for human CCL2 and CXCL10 were analyzed by real-time PCR and ELISA, respectively. p38 MAP kinase activation was evaluated by western blotting. Tacrolimus (1 µM) suppressed tumor necrosis factor (TNF)-α-induced CCL2 and CXCL10 mRNA expression, but did not modulate TNF-α-induced interleukin (IL)-6 or CXCL8 mRNA expression. Dose-dependent, inhibitory effects of tacrolimus on CCL2 and CXCL10 expression were observed at the mRNA and protein levels. Significant inhibitory effects of tacrolimus were observed at concentrations as low as 0.5 µM for CCL2 and 0.1 µM for CXCL10, respectively. TNF-α-induced CCL2 and CXCL10 expression depended on p38 MAP kinase activation, and tacrolimus strongly inhibited the TNF-α-induced phosphorylation of p38 MAP kinase. Tacrolimus did not affect interferon (IFN)-γ-induced signaling transducer and activator of transcription (STAT)-1 phosphorylation, nor did it modulate CXCL10 mRNA and protein expression. In conclusion, tacrolimus suppressed CCL2 and CXCL10 expression in human colonic myofibroblasts. These inhibitory effects of tacrolimus may play key roles in the therapeutic effects of colonic inflammation in inflammatory bowel disease (IBD) patients.

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Section: Discussionmentioning

confidence: 99%

Tacrolimus (FK506) suppresses TNF-α-induced CCL2 (MCP-1) and CXCL10 (IP-10) expression via the inhibition of p38 MAP kinase activation in human colonic myofibroblasts

Aomatsu

Imaeda

Takahashi

et al. 2012

International Journal of Molecular Medicine

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“…While tacrolimus has been reported to affect macrophages in IL-10 -/-mice, such as by inducing apoptosis and inhibiting cytokine production [26], the effective concentration (approximately 1 9 10 -5 or 1 9 10 -4 mol/L) was much higher than concentrations for inhibiting cytokines in activated T-cells, as shown in the present study, suggesting that tacrolimus exerted its effect against colitis in IL-10 -/-mice primarily by targeting infiltrated T-cells in the colon mucosa. Direct inhibition of T-cell activation by tacrolimus would then lead to indirect inhibition of activation of other types of cells, including macrophages, neutrophils, and plasma cells.…”

Section: Discussionmentioning

confidence: 99%

Preventive and therapeutic effects of tacrolimus in an interleukin-10-deficient mouse model of colitis

et al. 2011

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“…Cyclosporine and tacrolimus are calcineurin inhibitors that exert their immunomodulatory effect by inhibiting the production of interleukin-2, the activation of T lymphocytes and the function of macrophages [42][43][44]. Although some conflicting data exist [45], cyclosporine is used for severe steroid refractory UC, mainly at tertiary institutions, to avoid colectomy [46][47][48][49].…”

Section: Calcineurin Inhibitorsmentioning

confidence: 99%

Update on the Management of Ulcerative Colitis

Hoentjen

Sakuraba

Hanauer

2011

Curr Gastroenterol Rep

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The treatment options for inflammatory bowel disease have expanded with the introduction of biological therapies. Recently published controlled clinical trials were searched and those that impact the clinical management of ulcerative colitis (UC) are discussed in this review. In the management of mild to moderate UC, mesalamine still remains the first choice of drug. The newly developed once daily formulations have shown equal efficacy to divided doses and possibly portend better compliance owing to a simplified regimen. In outpatients with moderate to severe UC, recent data indicate that infliximab induced and maintained remission leads to decreased colectomy rates and fewer hospitalizations. An alternative anti-tumor necrosis factor (TNF) agent, adalimumab, was also recently shown to be effective for induction of remission in moderate to severe UC. The use of immunosuppressives, such as azathioprine and mercaptopurine, is associated with decreased colectomy rates and thioguanine was shown to be effective in maintaining clinical remission in those who are intolerant to azathioprine/mercaptopurine. In hospitalized patients with steroid resistant severe UC, infliximab and tacrolimus may be alternatives to cyclosporine in those who are otherwise candidates for colectomy. Adequate long-term maintenance therapy with immunosuppressives or anti-TNF therapy is required after rescue therapy for a sustained benefit. Future research is needed to position the available anti-TNF agents and combined immunosuppressive therapy in the treatment of UC to achieve and maintain steroid free remission.

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Immunosuppressive effects of tacrolimus on macrophages ameliorate experimental colitis

Abstract: Tacrolimus suppresses the function of activated macrophages and promotes their apoptosis, which may lead to the amelioration of colonic inflammation.

Cited by 64 publications

References 41 publications

Tacrolimus (FK506) suppresses TNF-α-induced CCL2 (MCP-1) and CXCL10 (IP-10) expression via the inhibition of p38 MAP kinase activation in human colonic myofibroblasts

Tacrolimus (FK506) suppresses TNF-α-induced CCL2 (MCP-1) and CXCL10 (IP-10) expression via the inhibition of p38 MAP kinase activation in human colonic myofibroblasts

Preventive and therapeutic effects of tacrolimus in an interleukin-10-deficient mouse model of colitis

Update on the Management of Ulcerative Colitis

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