Repairing effects of interleukin 11 (IL-11) towards high dose methotrexate-induced rat small intestinal mucositis and its impacts on T-lymphoblastic leukemia cell line

Document Type: Original Article


1 Department of Pediatrics, Liaocheng People's Hospital, Liaocheng 252000, Shandong, China

2 Departments of Pharmacy, the Fourth People's Hospital of Liaocheng, Liaocheng 252000, Shandong, China

3 Department of Pediatrics, Shandong Province-owned Hospital, Jinan 250021, Shandong, China


Objective(s): To investigate the efficacy of interleukin 11 (IL-11) towards the high dose methotrexate (HDMTX)-concurrent rat small intestinal mucositis and its impacts on the proliferation of the human T-lymphoblastic leukemia (CEM) cell line.
Materials and Methods:95 Wistar rats were randomly divided into five groups, the normal control group (A), the methotrexate (MTX) control group (B), the IL-11-pre-treated high-dose group (C), the post-IL-11-treatment high-dose group (D) and the post-IL-11-treatment low-dose group (E). After the intraperitoneal injection of MTX in the groups B-E, the rats were sacrificed at 1, 3, 5 and 7 days. The mortality, morphological and ultrastructural changes of small intestine of each group were observed. The cells were then cultured in vitro, and the MTT method was used to investigate the effects of different concentration of IL-11 on CEM proliferation and also on HDMTX-induced mucositis.
Results: IL-11 could reduce the intestinal histopathological score, increase the height of small intestinal villi, promote the proliferation of intestinal lacunar cells and reduce the mortality rate of rats. The IL-11 pre-treatment group exhibited the best efficacies, demonstrating significant difference with the control group (P<0.01). In addition, the proliferation of CEM was not promoted, indicating that IL-11 could not inhibit HDMTX.
Conclusion: IL-11 could reduce the severity of HDMTX-induced intestinal mucositis, and improve the survival rate of experimental rats, and could be safely used as the adjuvant treatment of HDMTX in childhood leukemia.


1. Chabner BA, Devita VT. Anticancer drugs in cancer. Hellman S, Rosenberg SA. editors. Principles and Practice of Oncology. 4th ed. 1995.p. 325-417.

2. Kapoor G, Sinha R, Abedin S. Experience with high dose methotrexate therapy in childhood acute lymphoblastic leukemia in a tertiary care cancer centre of a developing country. Pediatr Blood Cancer 2012; 59:448-453.

3. Xian CJ, Corper R, Howarth GS, Read LC, Kallincos NC. Incread expression of HGF and c-met in rat small intestinal during recovery from methotrexate-induced mucositis. Br J Cancer 2000; 82:945-952.

4. Howarth GS, Cool TC, Bourne AJ, Ballard FJ, Read LC. Insuline-like growth factor-I (IGF-I) stimulates regrowth of the damaged intestine in rats, when administered following, but not concurrent with methotrexate. Growth Factors 1998; 15:279-292.

5. Xian CJ, Howarth GS, Mardell CE, Cool JC, Familari M, Read LC, et al. Temporal changes in TFF3 expression and jejunal morphology during methotrexate-induced damage and repair. Am J Physiol 1999; 277:G785-795.

6. Zheng C, Cotrim AP, Sunshine AN, Sugito T, Liu L, Sowers A, et al. Prevention of radiation-induced oral mucositis after adenoviral vector-mediated transfer of the keratinocyte growth factor cDNA to mouse submandibular glands. Clin Cancer Res 2009; 15:4641-4648.

7. Ceccarelli S, Romano F, Angeloni A, Marchese C. Potential dual role of KGF/KGFR as a target option in novel therapeutic strategies for the treatment of cancers and mucosal damages. Export Opin Ther Targets 2012; 16:377-393.

8. Ben-Lulu S, Pollak Y, Mogilner J, Bejar J, G Coran A, Sukhotnik I. Dietary transforming growth factor-beta 2 (TGF-β2) supplementation reduces methotrexate-induced intestinal mucosal injury in a rat. PLoS One 2012; 7:e45221.

9. Raber-Durlacher JE, von Bültzingslöwen I, Logan RM, Bowen J, Al-Azri AR, Everaus H, et al. Systematic review of cytokines and growth factors for the management of oral mucositis in cancer patients. Suport Care Cancer 2013; 21:343-355.

10. Worthington HV, Clarkson JE, Bryan G, Furness S, Glenny AM, Littlewood A, et al. Interventions for preventing oral mucositis for patients with cancer receiving treatment. Cochrane Database Syst Rev 2011; CD000978.

11. Sukhotnik I, Pollak Y, Coran AG, Pilatov J, Bejar J, Mogilner JG, et al. Glutamine attenuates the inhibitory effect of methotrexate on TLR signaling during intestinal chemotherapy-induced mucositis in a rat. Nutr Metab (Lond) 2014; 11:17.

12. Sukhotnik I, Mogilner JG, Karry R, Shamian B, Lurie M, Kokhanovsky N, et al. Effect of oral glutamine on enterocyte turnover during methotrexate-induced mucositis in rats. Digestion 2009; 79:5-13.

13. Gu J, Zhu S, Li X, Wu H, Li Y, Hua F. Effect of amifostine in head and neck cancer patients treated with radiotherapy: a systematic review and meta-analysis based on randomized controlled trials. PLoS One 2014; 9:e95968.

14. Chen C, Tian L, Zhang M, Sun Q, Zhang X, Li X, et al. Protective effect of amifostine on high-dose methotrexate-induced small intestinal mucositis in mice. Dig Dis Sci 2013; 58:3134-3143.

15. Morón-Medina A, Viera N, de Morales TR, Alcocer S, Bohorquez D. Methotrexate as inducer of proinflammatory cytokines by epithelial cells. Invest Clin 2014; 55:15-22.

16. Gibson RJ, Keefe DM, Thompson FM, Clarke JM, Goland GJ, Cummins AG. Effect of interleukin-11 on ameliorating intestinal damage after methotrexate treament of breast cancer in rats. Dig Dis Sci 2002; 47:2751-2757.

17. Yang L, Hu X, Xu L. Impact of methylenetetra-hydrofolate reductase (MTHFR) polymorphisms on methotrexate-induced toxicities in acute lymphoblastic leukemia: a meta-analysis. Tumour Biol 2012; 33:1445-1454.

18. Du XX, Doerschuk CM, Orazi A, Williams DA. A bone marrow stromal-derived growth factor, interleukin-11, stimulates recovery of small intestinal mucosal cells after cytoablative therapy. Blood 1994; 83:33-37.

19. Wen CY, Ito M, Matsuu M, Fukuda E, Shichijo K, Nakashima M, et al. Mechanism of the antiulcerogenic effect of IL-11 on acetic acid-induced gastric ulcer in rats. Life Sci 2002; 70:2997-3005.

20. Sonis ST, Person RL, Edward LJ, Lucey CA, Wang L, Mason L, et al. Defining mechanisms of action of interleukin-11 on the progression of radiation-induced oral mucositis in hamsters. Oral Oncol 2000; 36:373-381.

21. Chinese Pediatric Society, Chinese Medical Association. Diagnosis and treatment of acute lymphoblastic leukemia of childhood (The Fourth revised draft). Chin J Pediatr 2014; 52:641-644.

22. Schwertschlag US, Trepicchio WL, Dykstra KH,   Keith JC, Turner KJ, Dorner AJ. Hematopoietic, immunomodulatory and epithelial effect of interleukin-11. Leukemia 1999; 13:1307-1315.

23. Peterson RL, Bozza MM, Dorner AJ. Interleukin-11 induces intestinal epithelial cell growth arrest through effects on retinoblastoma protein phosphorylation. Am J Pathol 1996; 149:895-902.