This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Belizario, J. E. Articles by Dinarello, C. A. Search for Related Content PubMed PubMed Citation Articles by Belizario, J. E. Articles by Dinarello, C. A.

Interleukin 1, Interleukin 6, Tumor Necrosis Factor, and Transforming Growth Factor ß Increase Cell Resistance to Tumor Necrosis Factor Cytotoxicity by Growth Arrest in the G₁ Phase of the Cell Cycle¹

Department of Medicine, Tufts University School of Medicine, and New England Medical Center, Boston, Massachusetts 02111

During infection, inflammation, immune responses, and neoplastic growth, various cytokines are produced affecting both susceptibility to and protection from cellular death. We have studied the protective effect of pretreatment of the L929 fibroblast cell line with interleukin 1ß (IL-1ß), IL-6, tumor necrosis factor (TNF-), or transforming growth factor ß₁ (TGF-ß) on subsequent TNF/actinomycin D-induced cytotoxicity. The protective effects of these cytokines on TNF cytotoxicity were time and concentration dependent. TGF-ß was the most effective cytokine, followed by TNF, IL-1ß, and IL-6. Activators of protein kinase C also afforded protection, and TGF-ß acted synergistically with either phorbol 12-myristate 13-acetate or the calcium ionophore A-23187. TGF-ß-induced protection against TNF was observed in cells subjected to prolonged treatment with phorbol 12-myristate 13-acetate. Cells pretreated with prostaglandin E₂ or cholera toxin amplified the sensitivity to TNF and inhibited TGF-ß-mediated resistance, whereas indomethacin enhanced the protective effect of TGF-ß. Cells cultured in the presence of IL-1ß, IL-6, TNF-, or TGF-ß for 6 h inhibited DNA synthesis, and this was associated with concomitant growth arrest in the G₁ phase of the cell cycle. On the other hand, prostaglandin E₂ or cholera toxin stimulated the progression of cells from G₁ toward G₂ + M which was associated with increased TNF sensitivity. We conclude that these cytokines protect against death by arresting growth in the G₁ phase of the cell cycle.

¹ This study is supported by NIH Grant AI-15614. J. E. B. is supported by a Fellowship of the Ministry of Science and Technology of Brazil (CNPq).

² To whom requests for reprints should be addressed, at the Department of Medicine, New England Medical Center, 750 Washington St. Boston, MA 02111.

Received 8/30/90. Accepted 2/22/91.

This article has been cited by other articles:

				R. S. Muraoka-Cook, H. Kurokawa, Y. Koh, J. T. Forbes, L. R. Roebuck, M. H. Barcellos-Hoff, S. E. Moody, L. A. Chodosh, and C. L. Arteaga Conditional Overexpression of Active Transforming Growth Factor {beta}1 In vivo Accelerates Metastases of Transgenic Mammary Tumors Cancer Res., December 15, 2004; 64(24): 9002 - 9011. [Abstract] [Full Text] [PDF]

				S. G. Agrawal, J. Marquet, J. Plumas, H. Rouard, M.-H. Delfau-Larue, P. Gaulard, L. Boumsell, F. Reyes, A. Bensussan, and J.-P. Farcet Multiple co-stimulatory signals are required for triggering proliferation of T cells from human secondary lymphoid tissue Int. Immunol., April 1, 2001; 13(4): 441 - 450. [Abstract] [Full Text] [PDF]

				S. W. Tobin, M. K. Brown, K. Douville, D. C. Payne, A. Eastman, and B. A. Arrick Inhibition of Transforming Growth Factor {beta} Signaling in MCF-7 Cells Results in Resistance to Tumor Necrosis Factor {{alpha}}: A Role for Bcl-2 Cell Growth Differ., February 1, 2001; 12(2): 109 - 117. [Abstract] [Full Text]

				W. H. Wilson, L. Sorbara, W. D. Figg, E. K. Mont, E. Sausville, K. E. Warren, F. M. Balis, K. Bauer, M. Raffeld, A. M. Senderowicz, et al. Modulation of Clinical Drug Resistance in a B Cell Lymphoma Patient by the Protein Kinase Inhibitor 7-Hydroxystaurosporine: Presentation of a Novel Therapeutic Paradigm Clin. Cancer Res., February 1, 2000; 6(2): 415 - 421. [Abstract] [Full Text]

				R. L. Chelvarajan, N. L. Gilbert, and S. Bondada Neonatal Murine B Lymphocytes Respond to Polysaccharide Antigens in the Presence of IL-1 and IL-6 J. Immunol., October 1, 1998; 161(7): 3315 - 3324. [Abstract] [Full Text] [PDF]

				F.-h. Xu, S. Sharma, A. Gardner, Y. Tu, A. Raitano, C. Sawyers, and A. Lichtenstein Interleukin-6-Induced Inhibition of Multiple Myeloma Cell Apoptosis: Support for the Hypothesis That Protection Is Mediated Via Inhibition of the JNK/SAPK Pathway Blood, July 1, 1998; 92(1): 241 - 251. [Abstract] [Full Text] [PDF]

				N. J. Donato and M. Perez Tumor Necrosis Factor-induced Apoptosis Stimulates p53 Accumulation and p21WAF1 Proteolysis in ME-180 Cells J. Biol. Chem., February 27, 1998; 273(9): 5067 - 5072. [Abstract] [Full Text] [PDF]

				T. Bellido, V. Z. C. Borba, P. Roberson, and S. C. Manolagas Activation of the Janus Kinase/STAT (Signal Transducer and Activator of Transcription) Signal Transduction Pathway by Interleukin-6-Type Cytokines Promotes Osteoblast Differentiation Endocrinology, September 1, 1997; 138(9): 3666 - 3676. [Abstract] [Full Text] [PDF]

				Y. Furukawa, S. Iwase, Y. Terui, J. Kikuchi, T. Sakai, M. Nakamura, S. Kitagawa, and M. Kitagawa Transcriptional Activation of the cdc2 Gene Is Associated with Fas-induced Apoptosis of Human Hematopoietic Cells J. Biol. Chem., November 8, 1996; 271(45): 28469 - 28477. [Abstract] [Full Text] [PDF]

				C. Borner and C. Borner Diminished Cell Proliferation Associated with the Death-protective Activity of Bcl-2 J. Biol. Chem., May 31, 1996; 271(22): 12695 - 12698. [Abstract] [Full Text] [PDF]

				W. Meikrantz and R. Schlegel Suppression of Apoptosis by Dominant Negative Mutants of Cyclin-dependent Protein Kinases J. Biol. Chem., April 26, 1996; 271(17): 10205 - 10209. [Abstract] [Full Text] [PDF]

				S. Muthukkumar, S. F. Sells, S. A. Crist, and V. M. Rangnekar Interleukin-1 Induces Growth Arrest by Hypophosphorylation of the Retinoblastoma Susceptibility Gene Product RB J. Biol. Chem., March 8, 1996; 271(10): 5733 - 5740. [Abstract] [Full Text] [PDF]

				N.-S. Chang and N. S. Chang Transforming Growth Factor-beta1 Induction of Novel Extracellular Matrix Proteins That Trigger Resistance to Tumor Necrosis Factor Cytotoxicity in Murine L929 Fibroblasts J. Biol. Chem., March 31, 1995; 270(13): 7765 - 7772. [Abstract] [Full Text] [PDF]