The Common Chain (c) Is a Required Signaling Component of the I
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- 作者：Tania Habib ; Shantha Senadheera ; Kenneth Weinberg ; and Kenneth Kaushansky
- 刊名：Biochemistry
- 出版年：2002
- 出版时间：July 9, 2002
- 年：2002
- 卷：41
- 期：27
- 页码：8725 - 8731
- 全文大小：82K
- 年卷期：v.41,no.27(July 9, 2002)
- ISSN：1520-4995
文摘
The common cytokine receptor 
chain (c), an essential component of the receptors for IL-2, IL-4, IL-7, IL-9, and IL-15, is critical for the development and function of lymphocytes. Recently, anovel lymphokine (IL-21) and its receptor (IL-21R
) were described which profoundly affect the growthand activation state of B, T, and NK cells in concert with other lymphokines or stimuli [Parrish-Novak,J., et al. (2000) Nature 408, 57-63]. In this report, we show that c is also a required signaling componentof the IL-21 receptor (IL-21R) using the c-deficient X-linked severe combined immunodeficiency (XSCID)lymphoblastoid cell line JT, and JT cells reconstituted with c (JT/c). Moreover, we demonstrate afunctional requirement for both c and the c-associated Janus family tyrosine kinase 3 (JAK3) in IL-21-induced proliferation of pro-B-lymphoid cells engineered to express human IL-21R (BaF3/IL-21R).Retroviral-mediated transduction of wild-type c into XSCID JT cells restored function to the IL-21R, asshown by IL-21-induced tyrosine phosphorylation of JAK1 and JAK3, and downstream activation ofSTAT5, in JT/c cells as well as BaF3/IL-21R and primary splenic B cells. In contrast, IL-21 failed toactivate the JAK-STAT pathway in nonreconstituted JT cells. Monoclonal antibodies specific for the cchain effectively inhibited IL-21-induced growth of BaF3/IL-21R cells, supporting a functional role forthis molecule in the IL-21R complex. In addition, the specific JAK3 tyrosine kinase inhibitor WHI-P131significantly reduced IL-21-induced proliferation of BaF3/IL-21R cells. Taken together, these resultsdefinitively demonstrate that IL-21-mediated signaling requires the c chain, and indicate that JAK3 isan essential transducer of c-dependent survival and/or mitogenic signals induced by this cytokine.
chain (c), an essential component of the receptors for IL-2, IL-4, IL-7, IL-9, and IL-15, is critical for the development and function of lymphocytes. Recently, anovel lymphokine (IL-21) and its receptor (IL-21R) were described which profoundly affect the growthand activation state of B, T, and NK cells in concert with other lymphokines or stimuli [Parrish-Novak,J., et al. (2000) Nature 408, 57-63]. In this report, we show that c is also a required signaling componentof the IL-21 receptor (IL-21R) using the c-deficient X-linked severe combined immunodeficiency (XSCID)lymphoblastoid cell line JT, and JT cells reconstituted with c (JT/c). Moreover, we demonstrate afunctional requirement for both c and the c-associated Janus family tyrosine kinase 3 (JAK3) in IL-21-induced proliferation of pro-B-lymphoid cells engineered to express human IL-21R (BaF3/IL-21R).Retroviral-mediated transduction of wild-type c into XSCID JT cells restored function to the IL-21R, asshown by IL-21-induced tyrosine phosphorylation of JAK1 and JAK3, and downstream activation ofSTAT5, in JT/c cells as well as BaF3/IL-21R and primary splenic B cells. In contrast, IL-21 failed toactivate the JAK-STAT pathway in nonreconstituted JT cells. Monoclonal antibodies specific for the cchain effectively inhibited IL-21-induced growth of BaF3/IL-21R cells, supporting a functional role forthis molecule in the IL-21R complex. In addition, the specific JAK3 tyrosine kinase inhibitor WHI-P131significantly reduced IL-21-induced proliferation of BaF3/IL-21R cells. Taken together, these resultsdefinitively demonstrate that IL-21-mediated signaling requires the c chain, and indicate that JAK3 isan essential transducer of c-dependent survival and/or mitogenic signals induced by this cytokine.