Abstract
Purpose
The aim of this study was to investigate the relationship between changes in IL-1β expression and intestinal apoptosis after chemotherapy. And we further determine whether interleukin-1 receptor antagonist (IL-1Ra) reduces apoptosis in vivo after 5-fluorouracil (5-FU) chemotherapy in the small intestine.
Methods
Intestinal mucositis was induced in mice by intraperitoneal injection of a single dose of 5-FU (200 mg/kg). IL-1Ra (1 mg/kg) was injected subcutaneously twice daily after 5-FU injection. 5-FU-induced intestinal apoptosis was detected by TUNEL assay. The expression of IL-1β induced by 5-FU in local intestinal tissue was examined by RT-PCR and immunohistochemistry. Assessment of 5-FU-induced mucositis (histology, diarrhea scores, bowel weight) was performed. The apoptosis-related proteins were investigated by western blotting analysis. The proliferation of intestine was examined by immunohistological staining of PCNA. Viability of IEC-6 cells was determined using the CCK-8 assay. The apoptosis of IEC-6 cells was examined by Hoechst 33342 staining.
Results
The variation of IL-1β expression induced by 5-FU was in accordance with the changes in intestinal apoptosis. Administration of IL-1Ra could block the destructive effect of IL-1β and reduce apoptosis in the small intestinal crypt after chemotherapy. The protection against apoptosis was in accordance with the reduction of the up-regulation of Bax and caspase 3 and the elimination of the down-regulation of Bcl-2 and Bcl-xL. Moreover, IL-1Ra attenuated the severity of intestinal mucositis induced by 5-FU and enhanced intestinal crypt proliferation. In vitro experiments showed that IL-1Ra suppressed apoptosis and increased cell viability in enterocyte IEC-6 cells treated with 5-FU. Additionally, IL-1Ra did not affect the chemotherapeutic effect of 5-FU in tumor CT-26 xenograft mice.
Conclusions
Our studies elucidate that IL-1β is quite possibly involved in and mediated the course of intestinal apoptosis after 5-FU chemotherapy. Administered with IL-1Ra protects mice against intestinal apoptosis induced by 5-FU, relieves mucosal impairment of the small intestine, and facilitates the recovery of the intestinal mucosa. IL-1Ra treatment offers a novel promising strategy for the prevention and cure of chemotherapy-induced intestinal mucositis in clinical practice.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Explore related subjects
Discover the latest articles and news from researchers in related subjects, suggested using machine learning.References
Bowen JM, Gibson RJ, Cummins AG et al (2006) Intestinal mucositis: the role of the Bcl-2 family, p53 and caspases in chemotherapy-induced damage. Support Care Cancer 14:713–731
Benson AB 3rd, Ajani JA, Catalano RB et al (2004) Recommended guidelines for the treatment of cancer treatment-induced diarrhea. J Clin Oncol 22:2918–2926
Symonds RP (1998) Treatment-induced mucositis: an old problem with new remedies. Br J Cancer 77:1689–1695
Watson AJ (1995) Necrosis and apoptosis in the gastrointestinal tract. Gut 37:165–167
Inomata A, Horii I, Suzuki K (2002) 5-Fluorouracil-induced intestinal toxicity: what determines the severity of damage to murine intestinal crypt epithelia? Toxicol Lett 133:231–240
Pritchard DM, Potten CS, Hickman JA et al (1998) The relationships between p53-dependent apoptosis, inhibition of proliferation, and 5-fluorouracil-induced histopathology in murine intestinal epithelia. Cancer Res 58:5453–5465
Anilkumar TV, Sarraf CE, Hunt T et al (1992) The nature of cytotoxic drug-induced cell death in murine intestinal crypts. Br J Cancer 65:552–558
Keefea DM, Brealey J, Goland GJ et al (2000) Chemotherapy for cancer causes apoptosis that precedes hypoplasia in crypts of the small intestine in humans. Gut 47:632–637
Logan RM, Gibson RJ, Bowen JM et al (2008) Characterisation of mucosal changes in the alimentary tract following administration of irinotecan: implications for the pathobiology of mucositis. Cancer Chemother Pharmacol 62:33–41
Logan RM, Stringer AM, Bowen JM et al (2008) Serum levels of NF-kappaB and pro-inflammatory cytokines following administration of mucotoxic drugs. Cancer Biol Ther 7:1139–1145
Giannoukakis N, Rudert WA, Ghivizzani SC et al (1999) Adenoviral gene transfer of the interleukin-1 receptor antagonist protein to human islets prevents IL-1beta-induced beta-cell impairment and activation of islet cell apoptosis in vitro. Diabetes 48:1730–1736
Holmin S, Mathiesen T (2000) Intracerebral administration of interleukin-1beta and induction of inflammation, apoptosis, and vasogenic edema. J Neurosurg 92:108–120
Nesic O, Xu GY, McAdoo D et al (2001) IL-1 receptor antagonist prevents apoptosis and caspase-3 activation after spinal cord injury. J Neurotrauma 18:947–956
Fortunato SJ, Menon R (2003) IL-1 beta is a better inducer of apoptosis in human fetal membranes than IL-6. Placenta 24:922–928
Ing DJ, Zang J, Dzau VJ et al (1999) Modulation of cytokine-induced cardiac myocyte apoptosis by nitric oxide, Bak, and Bcl-x. Circ Res 84:21–33
Mahr S, Neumayer N, Gerhard M et al (2000) IL-1beta-induced apoptosis in rat gastric enterochromaffin-like cells is mediated by iNOS, NF-kappaB, and Bax protein. Gastroenterology 118:515–524
Bowen JM, Gibson RJ, Keefe DM et al (2005) Cytotoxic chemotherapy upregulates pro-apoptotic Bax and Bak in the small intestine of rats and humans. Pathology 37:56–62
Kitada S, Krajewski S, Miyashita T et al (1996) Gamma-radiation induces upregulation of Bax protein and apoptosis in radiosensitive cells in vivo. Oncogene 12:187–192
Nita ME, Nagawa H, Tominaga O et al (1998) 5-Fluorouracil induces apoptosis in human colon cancer cell lines with modulation of Bcl-2 family proteins. Br J Cancer 78:986–992
Dinarello CA (1997) Interleukin-1. Cytokine Growth Factor Rev 8:253–265
Dewberry RM, King A, Crossman D et al (2008) Interleukin-1 receptor antagonist (IL-1ra) modulates endothelial cell proliferation. FEBS Lett 582:886–890
Abbate A, Salloum FN, Vecile E et al (2008) Anakinra, a recombinant human interleukin-1 receptor antagonist, inhibits apoptosis in experimental acute myocardial infarction. Circulation 117:2670–2683
Sun CC, Pang JH, Cheng CY et al (2006) Interleukin-1 receptor antagonist (IL-1RA) prevents apoptosis in ex vivo expansion of human limbal epithelial cells cultivated on human amniotic membrane. Stem Cells 24:2130–2139
Gibson RJ, Bowen JM, Inglis MR et al (2003) Irinotecan causes severe small intestinal damage, as well as colonic damage, in the rat with implanted breast cancer. J Gastroenterol Hepatol 18:1095–1100
Potten CS, Grant HK (1998) The relationship between ionizing radiation-induced apoptosis and stem cells in the small and large intestine. Br J Cancer 78:993–1003
Rusai K, Huang H, Sayed N et al (2008) Administration of interleukin-1 receptor antagonist ameliorates renal ischemia-reperfusion injury. Transpl Int 21:572–580
Chirivi RG, Garofalo A, Padura IM et al (1993) Interleukin 1 receptor antagonist inhibits the augmentation of metastasis induced by interleukin 1 or lipopolysaccharide in a human melanoma/nude mouse system. Cancer Res 53:5051–5054
McKenzieR C, Oran A, Dinarello CA et al (1996) Interleukin-1 receptor antagonist inhibits subcutaneous B16 melanoma growth in vivo. Anticancer Res 16:437–441
Estrov Z, Kurzrock R, Estey E et al (1992) Inhibition of acute myelogenous leukemia blast proliferation by interleukin-1 (IL-1) receptor antagonist and soluble IL-1 receptors. Blood 79:1938–1945
Author information
Authors and Affiliations
Corresponding author
Additional information
Z.-Q. Wu, X.-D. Han contributed equally to this article.
Rights and permissions
About this article
Cite this article
Wu, ZQ., Han, XD., Wang, Y. et al. Interleukin-1 receptor antagonist reduced apoptosis and attenuated intestinal mucositis in a 5-fluorouracil chemotherapy model in mice. Cancer Chemother Pharmacol 68, 87–96 (2011). https://doi.org/10.1007/s00280-010-1451-5
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00280-010-1451-5