HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Behbod, F. Articles by Kirken, R. A. Search for Related Content PubMed PubMed Citation Articles by Behbod, F. Articles by Kirken, R. A.

Concomitant Inhibition of Janus Kinase 3 and Calcineurin-Dependent Signaling Pathways Synergistically Prolongs the Survival of Rat Heart Allografts¹

Fariba Behbod^2,*, Rebecca A. Erwin-Cohen^2,*, Mou-Er Wang, Barton W. Trawick, Xienui Qu, Regina Verani, Barry D. Kahan, Stanislaw M. Stepkowski and Robert A. Kirken^3,*

^* Department of Integrative Biology and Pharmacology and Division of Immunology and Organ Transplantation, Department of Surgery, University of Texas Medical School, Houston, TX 77030

The cytoplasmic localized Janus tyrosine kinase 3 (Jak3) is activated by multiple cytokines, including IL-2, IL-4, and IL-7, through engagement of the IL-2R common -chain. Genetic inactivation of Jak3 is manifested as SCID in humans and mice. These findings have suggested that Jak3 represents a pharmacological target to control certain lymphoid-derived diseases. Using the rat T cell line Nb2-11c, we document that tyrphostin AG-490 blocked in vitro IL-2-induced cell proliferation (IC₅₀ 20 µM), Jak3 autophosphorylation, and activation of its key substrates, Stat5a and Stat5b, as measured by tyrosine/serine phosphorylation analysis and DNA-binding experiments. To test the notion that inhibition of Jak3 provides immunosuppressive potential, a 7-day course of i.v. therapy with 5–20 mg/kg AG-490 was used to inhibit rejection of heterotopically transplanted Lewis (RT1^l) heart allografts in ACI (RT1^a) recipients. In this study, we report that AG-490 significantly prolonged allograft survival, but also acted synergistically when used in combination with the signal 1 inhibitor cyclosporin A, but not the signal 3 inhibitor, rapamycin. Finally, AG-490 treatment reduced graft infiltration of mononuclear cells and Stat5a/b DNA binding of ex vivo IL-2-stimulated graft infiltrating of mononuclear cells, but failed to affect IL2R expression, as judged by RNase protection assays. Thus, inhibition of Jak3 prolongs allograft survival and also potentiates the immunosuppressive effects of cyclosporin A, but not rapamycin.

This article has been cited by other articles:

				S. M. Stepkowski, J. Kao, M.-E. Wang, N. Tejpal, H. Podder, L. Furian, J. Dimmock, A. Jha, U. Das, B. D. Kahan, et al. The Mannich Base NC1153 Promotes Long-Term Allograft Survival and Spares the Recipient from Multiple Toxicities J. Immunol., October 1, 2005; 175(7): 4236 - 4246. [Abstract] [Full Text] [PDF]

				P. F. Halloran Immunosuppressive Drugs for Kidney Transplantation N. Engl. J. Med., December 23, 2004; 351(26): 2715 - 2729. [Full Text] [PDF]

				Y. Wang, M. G. Malabarba, Z. S. Nagy, and R. A. Kirken Interleukin 4 Regulates Phosphorylation of Serine 756 in the Transactivation Domain of Stat6: ROLES FOR MULTIPLE PHOSPHORYLATION SITES AND Stat6 FUNCTION J. Biol. Chem., June 11, 2004; 279(24): 25196 - 25203. [Abstract] [Full Text] [PDF]

				P. S. Changelian, M. E. Flanagan, D. J. Ball, C. R. Kent, K. S. Magnuson, W. H. Martin, B. J. Rizzuti, P. S. Sawyer, B. D. Perry, W. H. Brissette, et al. Prevention of Organ Allograft Rejection by a Specific Janus Kinase 3 Inhibitor Science, October 31, 2003; 302(5646): 875 - 878. [Abstract] [Full Text] [PDF]

				F. Behbod, Z. S. Nagy, S. M. Stepkowski, J. Karras, C. R. Johnson, W. D. Jarvis, and R. A. Kirken Specific Inhibition of Stat5a/b Promotes Apoptosis of IL-2-Responsive Primary and Tumor-Derived Lymphoid Cells J. Immunol., October 15, 2003; 171(8): 3919 - 3927. [Abstract] [Full Text] [PDF]

				Z. S. Nagy, Y. Wang, R. A. Erwin-Cohen, J. Aradi, B. Monia, L. H. Wang, S. M. Stepkowski, H. Rui, and R. A. Kirken Interleukin-2 family cytokines stimulate phosphorylation of the Pro-Ser-Pro motif of Stat5 transcription factors in human T cells: resistance to suppression of multiple serine kinase pathways J. Leukoc. Biol., October 1, 2002; 72(4): 819 - 828. [Abstract] [Full Text] [PDF]

				S. M. Stepkowski, R. A. Erwin-Cohen, F. Behbod, M.-E. Wang, X. Qu, N. Tejpal, Z. S. Nagy, B. D. Kahan, and R. A. Kirken Selective inhibitor of Janus tyrosine kinase 3, PNU156804, prolongs allograft survival and acts synergistically with cyclosporine but additively with rapamycin Blood, January 15, 2002; 99(2): 680 - 689. [Abstract] [Full Text] [PDF]