Tacrolimus (FK506), a macrolide antibiotic with potent immunosuppressive effects was isolated from Streptomyces tsukubaensis and has been previously used to prevent allograft and for treatment of autoimmune disorders in humans[1-3].
Tacrolimus(FK506) (0-2 μM;24 h)reduces synthesis of type I collagen protein without affecting expression of collagen mRNAs in Human lung fibroblasts (HLFs)[8]. T cell proliferation in response to ligation of the T cell receptor is inhibited by tacrolimus(FK506) [4]. Ttacrolimus(FK506) (concentration gradient;48 h)inhibited oral squamous cell carcinoma (OSCC) progression in vitro [9].
Tacrolimus (FK506) was given intramuscularly at the dose of 0.5 and 1.0 mg/kg for three days before burn injury. Thermal trauma to the skin caused a statistically significant increase in MPO activity and MDA content in remote organs. Tacrolimus (FK506) was effective in reducing lipid peroxidation and neutrophil infiltration especially at 24 h postinjury in lung, liver and kidney[5]. Tacrolimus (FK506) has the ability to down-regulate free radical levels in severe ischemia-reperfusion liver, and tachlimus has also been shown to be an effective inhibitor of cytokine response[6]. A study on pulmonary fibrosis in mice suggested that FK506 can be a potent antifibrotic agent [7]. Tacrolimus (FK506) treatment inhibited activation of HSCs or reduced their number in the liver. In vivo, administration of Tacrolimus (FK506) at a dose of 4 mg/kg(i.p.; 4 weeks) completely prevented development of alcohol/carbon tetrachloride induced liver fibrosis in rats[8].
参考文献:
[1]. Wiederrecht G, Lam E, et,al. The mechanism of action of FK-506 and cyclosporin A. Ann N Y Acad Sci. 1993 Nov 30;696:9-19. doi: 10.1111/j.1749-6632.1993.tb17137.x. PMID: 7509138.
[2]. Kino T, Hatanaka H, et,al. FK-506, a novel immunosuppressant isolated from a Streptomyces. II. Immunosuppressive effect of FK-506 in vitro. J Antibiot (Tokyo). 1987 Sep;40(9):1256-65. doi: 10.7164/antibiotics.40.1256. PMID: 2445722.
[3]. Kondo H, Abe T, et,al. Efficacy and safety of tacrolimus (FK506) in treatment of rheumatoid arthritis: a randomized, double blind, placebo controlled dose-finding study. J Rheumatol. 2004 Feb;31(2):243-51. PMID: 14760792.
[4]. Thomson AW, Bonham CA, et,al.Mode of action of tacrolimus (FK506): molecular and cellular mechanisms. Ther Drug Monit. 1995 Dec;17(6):584-91. doi: 10.1097/00007691-199512000-00007. PMID: 8588225.
[5]. Cetinkale O, Konuko?lu D, et,al. Modulating the functions of neutrophils and lipid peroxidation by FK506 in a rat model of thermal injury. Burns. 1999 Mar;25(2):105-12. doi: 10.1016/s0305-4179(98)00147-8. PMID: 10208383.
[6]. Garcia-Criado FJ, Palma-Vargas JM, et,al.Tacrolimus (FK506) down-regulates free radical tissue levels, serum cytokines, and neutrophil infiltration after severe liver ischemia. Transplantation. 1997 Aug 27;64(4):594-8. doi: 10.1097/00007890-199708270-00008. PMID: 9293871.
[7]. Nagano J, Iyonaga K, et,al.Use of tacrolimus, a potent antifibrotic agent, in bleomycin-induced lung fibrosis. Eur Respir J. 2006 Mar;27(3):460-9. doi: 10.1183/09031936.06.00070705. PMID: 16507844.
[8]. Manojlovic Z, Blackmon J, et,al.Tacrolimus (FK506) prevents early stages of ethanol induced hepatic fibrosis by targeting LARP6 dependent mechanism of collagen synthesis. PLoS One. 2013 Jun 3;8(6):e65897. doi: 10.1371/journal.pone.0065897. PMID: 23755290; PMCID: PMC3670911.
[9]: Li Y, Wang Y, et,al. Tacrolimus inhibits oral carcinogenesis through cell cycle control. Biomed Pharmacother. 2021 Jul;139:111545. doi: 10.1016/j.biopha.2021.111545. Epub 2021 Apr 16. PMID: 33873145.
他克莫司 (FK506) 是一种具有强效免疫抑制作用的大环内酯类抗生素，从筑波链霉菌中分离出来，以前曾用于预防人类同种异体移植和治疗自身免疫性疾病[1-3]。< /p>\n
他克莫司 (FK506)（0-2 μM；24 小时）减少 I 型胶原蛋白的合成，而不影响人肺成纤维细胞 (HLF) 中胶原蛋白 mRNA 的表达[8]。他克莫司 (FK506) 抑制响应于 T 细胞受体连接的 T 细胞增殖 [4]。 Ttacrolimus(FK506)（浓度梯度；48 h）体外抑制口腔鳞状细胞癌（OSCC）进展[9]。
在烧伤前三天，他克莫司 (FK506) 以 0.5 和 1.0 mg/kg 的剂量肌肉注射。皮肤的热损伤导致远端器官中 MPO 活性和 MDA 含量显着增加。他克莫司 (FK506) 可有效减少肺、肝和肾损伤后 24 小时的脂质过氧化和中性粒细胞浸润[5]。他克莫司 (FK506) 具有下调严重缺血再灌注肝脏中自由基水平的能力，而且他克莫司也被证明是一种有效的细胞因子反应抑制剂[6]。一项针对小鼠肺纤维化的研究表明，FK506 可能是一种有效的抗纤维化药物[7]。他克莫司 (FK506) 治疗可抑制 HSC 的激活或减少其在肝脏中的数量。在体内，以 4 mg/kg（i.p.；4 周）的剂量给予他克莫司 (FK506) 可完全阻止酒精/四氯化碳诱导的大鼠肝纤维化的发展[8]。
| Cell experiment [1]: | |
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Cell lines |
Human lung fibroblasts (HLFs) |
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Preparation Method |
Cells were incubated with the indicated concentrations of FK506 for 24 h. The cells were then washed 3 times with PBS and incubated for 3 h in serum free medium to accumulate secreted collagen. |
|
Reaction Conditions |
0-2 μM Tacrolimus (FK506);24 h |
|
Applications |
Tacrolimus (FK506) reduces synthesis of type I collagen protein. |
| Animal experiment [2]: | |
|
Animal models |
Male inbred alki Wistar rats weighing 150-200 g |
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Preparation Method |
At the start of the study, drinking water was replaced by 5% ethanol as the only source of liquid and the rats were allowed to drink at will. Carbon tetrachloride (CCl4) was administered intraperitoneally (i.p.) at 0.5 μl/g of CCl4 in mineral oil twice a week for 4 weeks. Tacrolimus (FK506) was dissolved in 200 μL of Cremaphor and injected at daily dose of 4 mg/kg for 4 weeks (28 days). Control animals received by i.p. injections the Cremaphor vehicle. The groups were as follows: group 1:5% ethanol liquid+CCl4 injections; group 2:5% ethanol liquid+CCl4 injections+FK506 treatment; group 3: FK506 treatment only; group 4: vehicle only. |
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Dosage form |
4 mg/kg;4 weeks (28 days);i.p. |
|
Applications |
Tacrolimus (FK506) treatment inhibited activation of hepatic stellate cells (HSC) or reduced their number in the liver. In vivo, administration of FK506 at a dose of 4 mg/kg completely prevented development of alcohol/carbon tetrachloride induced liver fibrosis in rats. |
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参考文献: [1].Manojlovic Z, Blackmon J, et,al. Tacrolimus (FK506) prevents early stages of ethanol induced hepatic fibrosis by targeting LARP6 dependent mechanism of collagen synthesis. PLoS One. 2013 Jun 3;8(6):e65897. doi: 10.1371/journal.pone.0065897. PMID: 23755290; PMCID: PMC3670911. |
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