Abstract
Recombinant human (rh) interleukin (IL)-11 has been shown to reduce gastrointestinal mucosal injury after chemotherapy or irradiation in several animal models. As reduction of cellular proliferation can be cytoprotective, we have examined the effect of rhIL-11 compared with transforming growth factor (TGF)-beta 1 on the proliferation and cell cycle progression of a rat intestinal cell line, IEC-6. IEC-6 cells treated with rhIL-11 or rhTGF-beta 1 exhibited a reduced proliferative rate as measured by cell counts and [3H]thymidine incorporation. The presence of neutralizing anti-TGF-beta 1 antibodies did not block the antiproliferative effect of rhIL-11 indicating that the rhIL-11 activity was not mediated through the induction of endogenous TGF-beta 1 production. Growth inhibition correlated with delayed entry into S phase of the cell cycle. Cell cycle arrest was associated with suppression of retinoblastoma protein phosphorylation. Transient cell cycle arrest is a possible mechanism by which rhIL-11 may protect intestinal epithelial cells from damage induced by chemotherapy or radiation therapy. This study provides a rationale for the clinical use of rhIL-11 to preserve the integrity of the gastrointestinal mucosa during cancer treatment regimens.
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- Barnard J. A., Beauchamp R. D., Coffey R. J., Moses H. L. Regulation of intestinal epithelial cell growth by transforming growth factor type beta. Proc Natl Acad Sci U S A. 1989 Mar;86(5):1578–1582. doi: 10.1073/pnas.86.5.1578. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ciacci C., Lind S. E., Podolsky D. K. Transforming growth factor beta regulation of migration in wounded rat intestinal epithelial monolayers. Gastroenterology. 1993 Jul;105(1):93–101. doi: 10.1016/0016-5085(93)90014-4. [DOI] [PubMed] [Google Scholar]
- Cone J. L., Brown D. R., DeLarco J. E. An improved method of purification of transforming growth factor, type beta from platelets. Anal Biochem. 1988 Jan;168(1):71–74. doi: 10.1016/0003-2697(88)90011-5. [DOI] [PubMed] [Google Scholar]
- Del Sal G., Ruaro M. E., Philipson L., Schneider C. The growth arrest-specific gene, gas1, is involved in growth suppression. Cell. 1992 Aug 21;70(4):595–607. doi: 10.1016/0092-8674(92)90429-g. [DOI] [PubMed] [Google Scholar]
- Dignass A. U., Podolsky D. K. Cytokine modulation of intestinal epithelial cell restitution: central role of transforming growth factor beta. Gastroenterology. 1993 Nov;105(5):1323–1332. doi: 10.1016/0016-5085(93)90136-z. [DOI] [PubMed] [Google Scholar]
- Dowdy S. F., Hinds P. W., Louie K., Reed S. I., Arnold A., Weinberg R. A. Physical interaction of the retinoblastoma protein with human D cyclins. Cell. 1993 May 7;73(3):499–511. doi: 10.1016/0092-8674(93)90137-f. [DOI] [PubMed] [Google Scholar]
- Du X. X., Doerschuk C. M., Orazi A., Williams D. A. A bone marrow stromal-derived growth factor, interleukin-11, stimulates recovery of small intestinal mucosal cells after cytoablative therapy. Blood. 1994 Jan 1;83(1):33–37. [PubMed] [Google Scholar]
- Du X. X., Williams D. A. Interleukin-11: a multifunctional growth factor derived from the hematopoietic microenvironment. Blood. 1994 Apr 15;83(8):2023–2030. [PubMed] [Google Scholar]
- Goodrich D. W., Wang N. P., Qian Y. W., Lee E. Y., Lee W. H. The retinoblastoma gene product regulates progression through the G1 phase of the cell cycle. Cell. 1991 Oct 18;67(2):293–302. doi: 10.1016/0092-8674(91)90181-w. [DOI] [PubMed] [Google Scholar]
- Hannon G. J., Beach D. p15INK4B is a potential effector of TGF-beta-induced cell cycle arrest. Nature. 1994 Sep 15;371(6494):257–261. doi: 10.1038/371257a0. [DOI] [PubMed] [Google Scholar]
- Harper J. W., Adami G. R., Wei N., Keyomarsi K., Elledge S. J. The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases. Cell. 1993 Nov 19;75(4):805–816. doi: 10.1016/0092-8674(93)90499-g. [DOI] [PubMed] [Google Scholar]
- Kato J. Y., Matsuoka M., Polyak K., Massagué J., Sherr C. J. Cyclic AMP-induced G1 phase arrest mediated by an inhibitor (p27Kip1) of cyclin-dependent kinase 4 activation. Cell. 1994 Nov 4;79(3):487–496. doi: 10.1016/0092-8674(94)90257-7. [DOI] [PubMed] [Google Scholar]
- Keith J. C., Jr, Albert L., Sonis S. T., Pfeiffer C. J., Schaub R. G. IL-11, a pleiotropic cytokine: exciting new effects of IL-11 on gastrointestinal mucosal biology. Stem Cells. 1994;12 (Suppl 1):79–90. [PubMed] [Google Scholar]
- Ko T. C., Sheng H. M., Reisman D., Thompson E. A., Beauchamp R. D. Transforming growth factor-beta 1 inhibits cyclin D1 expression in intestinal epithelial cells. Oncogene. 1995 Jan 5;10(1):177–184. [PubMed] [Google Scholar]
- Kurokowa M., Lynch K., Podolsky D. K. Effects of growth factors on an intestinal epithelial cell line: transforming growth factor beta inhibits proliferation and stimulates differentiation. Biochem Biophys Res Commun. 1987 Feb 13;142(3):775–782. doi: 10.1016/0006-291x(87)91481-1. [DOI] [PubMed] [Google Scholar]
- Laiho M., DeCaprio J. A., Ludlow J. W., Livingston D. M., Massagué J. Growth inhibition by TGF-beta linked to suppression of retinoblastoma protein phosphorylation. Cell. 1990 Jul 13;62(1):175–185. doi: 10.1016/0092-8674(90)90251-9. [DOI] [PubMed] [Google Scholar]
- Li Y., Jenkins C. W., Nichols M. A., Xiong Y. Cell cycle expression and p53 regulation of the cyclin-dependent kinase inhibitor p21. Oncogene. 1994 Aug;9(8):2261–2268. [PubMed] [Google Scholar]
- Polyak K., Kato J. Y., Solomon M. J., Sherr C. J., Massague J., Roberts J. M., Koff A. p27Kip1, a cyclin-Cdk inhibitor, links transforming growth factor-beta and contact inhibition to cell cycle arrest. Genes Dev. 1994 Jan;8(1):9–22. doi: 10.1101/gad.8.1.9. [DOI] [PubMed] [Google Scholar]
- Potten C. S. Interleukin-11 protects the clonogenic stem cells in murine small-intestinal crypts from impairment of their reproductive capacity by radiation. Int J Cancer. 1995 Jul 28;62(3):356–361. doi: 10.1002/ijc.2910620321. [DOI] [PubMed] [Google Scholar]
- Quaroni A., Wands J., Trelstad R. L., Isselbacher K. J. Epithelioid cell cultures from rat small intestine. Characterization by morphologic and immunologic criteria. J Cell Biol. 1979 Feb;80(2):248–265. doi: 10.1083/jcb.80.2.248. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Serrano M., Hannon G. J., Beach D. A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4. Nature. 1993 Dec 16;366(6456):704–707. doi: 10.1038/366704a0. [DOI] [PubMed] [Google Scholar]
- Sherr C. J. G1 phase progression: cycling on cue. Cell. 1994 Nov 18;79(4):551–555. doi: 10.1016/0092-8674(94)90540-1. [DOI] [PubMed] [Google Scholar]
- Sonis S. T., Costa J. W., Jr, Evitts S. M., Lindquist L. E., Nicolson M. Effect of epidermal growth factor on ulcerative mucositis in hamsters that receive cancer chemotherapy. Oral Surg Oral Med Oral Pathol. 1992 Dec;74(6):749–755. doi: 10.1016/0030-4220(92)90402-c. [DOI] [PubMed] [Google Scholar]
- Sonis S. T., Lindquist L., Van Vugt A., Stewart A. A., Stam K., Qu G. Y., Iwata K. K., Haley J. D. Prevention of chemotherapy-induced ulcerative mucositis by transforming growth factor beta 3. Cancer Res. 1994 Mar 1;54(5):1135–1138. [PubMed] [Google Scholar]
- Sonis S., Muska A., O'Brien J., Van Vugt A., Langer-Safer P., Keith J. Alteration in the frequency, severity and duration of chemotherapy-induced mucositis in hamsters by interleukin-11. Eur J Cancer B Oral Oncol. 1995 Jul;31B(4):261–266. doi: 10.1016/0964-1955(95)00015-a. [DOI] [PubMed] [Google Scholar]
- Toyoshima H., Hunter T. p27, a novel inhibitor of G1 cyclin-Cdk protein kinase activity, is related to p21. Cell. 1994 Jul 15;78(1):67–74. doi: 10.1016/0092-8674(94)90573-8. [DOI] [PubMed] [Google Scholar]
- Xiong Y., Hannon G. J., Zhang H., Casso D., Kobayashi R., Beach D. p21 is a universal inhibitor of cyclin kinases. Nature. 1993 Dec 16;366(6456):701–704. doi: 10.1038/366701a0. [DOI] [PubMed] [Google Scholar]
- Zhang H., Hannon G. J., Beach D. p21-containing cyclin kinases exist in both active and inactive states. Genes Dev. 1994 Aug 1;8(15):1750–1758. doi: 10.1101/gad.8.15.1750. [DOI] [PubMed] [Google Scholar]
- el-Deiry W. S., Tokino T., Velculescu V. E., Levy D. B., Parsons R., Trent J. M., Lin D., Mercer W. E., Kinzler K. W., Vogelstein B. WAF1, a potential mediator of p53 tumor suppression. Cell. 1993 Nov 19;75(4):817–825. doi: 10.1016/0092-8674(93)90500-p. [DOI] [PubMed] [Google Scholar]

