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Related Collections Immunobiology Signal Transduction Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 15 November 2001, Vol. 98, No. 10, pp. 3030-3034 IMMUNOBIOLOGY Protein tyrosine phosphatase C selectively inhibits interleukin-6- and interleukin- 10-induced JAK-STAT signaling Nobuhiro Tanuma, Hiroshi Shima, Koji Nakamura, and Kunimi Kikuchi From the Division of Biochemical Oncology and Immunology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan.     Abstract Top Abstract Introduction Materials and methods Results Discussion References Protein tyrosine phosphatase (PTP)  (PTP) exists as 2 forms generated by alternative promoter usage. It has recently been reported that a cytosolic isoform of PTP (PTPC) when over-expressed in murine M1 myeloid cells inhibits interleukin-6 (IL-6)- and leukemia inhibitory factor-induced activation of Janus kinsases (JAKs), thereby suppressing STAT3 tyrosine phosphorylation and STAT3 signaling. This study characterizes an inhibitory action of PTPC on IL-6 signaling and also reveals that PTPC inhibitory activity is independent of other potential negative regulators, such as SHP-2 and SOCS family proteins. Furthermore, it analyzes the selectivity of PTPC action toward several cytokines. On IL-6 stimulation, expression of PTPC-DA, a catalytically inactive mutant of PTPC, results in an earlier onset of STAT3 tyrosine phosphorylation, suggesting different modes of action between PTPC and other negative regulators. In addition, the study shows PTPC-DA enhances activation of STAT1 by IL-6 as well. In terms of specificity to cytokines, over-expressed PTPC also inhibits IL-10-induced tyrosine phosphorylation of STAT3 in M1 cells, whereas PTPC does not affect either interferon-- and interferon--induced tyrosine phosphorylation of STATs or expression of STAT transcriptional targets. Among cytokines tested, the inhibitory effect of PTPC is selective to IL-6- and IL-10-induced JAK-STAT signaling. (Blood. 2001;98:3030-3034) © 2001 by The American Society of Hematology.     Introduction Top Abstract Introduction Materials and methods Results Discussion References Numerous cellular functions, such as growth, differentiation, and cell death, are regulated by cytokines. It is well established that the Janus kinase (JAK)-STAT signaling pathway plays a pivotal role in signal transduction via cytokine receptors.1-4 To date 7 members of the STAT family of proteins have been identified in mammals, and each STAT protein has been implicated in intracellular signaling elicited by distinct cytokines.5 It has been shown that phosphotyrosine-based motifs residing in receptor subunits determine which particular STAT(s) is activated by a specific cytokine.6 Although the mechanisms of signal transmission through the JAK-STAT pathway have been extensively studied, negative regulation of such signaling has thus far not been well characterized. Studies have identified a suppressors of cytokine signaling (SOCS)/STAT-induced STAT inhibitor (SSI)/cytokine-inducible SH2-containing protein (CIS) family of proteins that inhibits cytokine-induced JAK-STAT signaling(s).7-9 Because SOCS/SSI/CIS expression is cytokine inducible, this family of proteins is supposed to form a negative feedback loop in cytokine signaling. Interleukin-10 (IL-10) is an 18-kD polypeptide that is mainly secreted from helper T cells, B cells, thymocytes, keratinocytes, activated monocytes, and macrophages.10 IL-10 acts on natural killer cells, B cells, T-helper lymphocyte 1 cells, monocytes, and macrophages to down-regulate and/or to limit their inflammatory and immune responses.10,11 On binding of IL-10 to the IL-10 receptor (IL-10-R), which belongs to the class II cytokine receptor family,12,13 receptor-associated JAK tyrosine kinases are activated and stimulate downstream signaling.14-18 JAK1, tyrosine kinase 2 (TYK2), and STAT3 are all involved in this signaling cascade.17,19 Activated STAT3 protein, for example, translocates to the nucleus and regulates specific gene expression. Protein tyrosine phosphatase (PTP)  (PTP) exists as 2 forms generated by alternative promoter usage from a single gene: a transmembrane (PTPM) and a cytosolic (PTPC) form (PTPC is also referred to as cyt-PTP.).20-22 Although PTPM is expressed in brain, testis, and lung, expression of PTPC is mainly restricted to hematopoietic tissues such as spleen, thymus, and peritoneal macrophages.21,22 PTPC expression is up-regulated during differentiation and/or activation of macrophages.21,22 Peretz et al23 have reported that PTPC/cyt-PTP is also expressed in Schwann cells. Targeted disruption of the PTP gene in mice (both isoforms are disrupted) revealed its essential role in regulation of myelination of Schwann cells.23 The role of PTPC/cyt-PTP in other cell types remains obscure. Recently, we reported that forced expression of PTPC suppresses IL-6- and leukemia inhibitory factor (LIF)-induced JAK activation of murine M1 leukemia cells.24 In this study, to further define the molecular mechanism of this suppression, we characterized PTPC-mediated suppression of IL-6 signaling and examined whether PTPC is a general inhibitor of cytokine signaling. We found that PTPC-mediated suppression is selective for certain JAK-STAT signaling pathways through corresponding cytokine receptors such as gp130 and IL-10-R. These findings shed light on the regulatory mechanisms of cytokine signaling.     Materials and methods Top Abstract Introduction Materials and methods Results Discussion References Materials Murine interferon  (IFN-) and IFN- were generous gifts of Dr T. Abo (Niigata University) and Dr T. Minagawa (Hokkaido University), respectively. Human IL-6 was provided by Ajinomoto (Yokohama, Japan). Mouse IL-10 was purchased from Peprotech (London, United Kingdom). Specific antibodies to phosphotyrosine 701 of STAT1 and STAT1 were obtained from New England Biolabs (Beverly, MA). IL-10 binding assay The levels of IL-10-Rs on the cells were assessed by an IL-10-R detection kit (Genzyme, Minneapolis, MN), following the instructions of the manufacturer. The signal due to binding of biotinylated IL-10 was almost completely abolished by addition of 5-fold excess of nonbiotinylated mouse IL-10 (data not shown). Stable transfectants Establishment of M1 clones stably expressing PTPC or PTPC-DA has been described elsewhere.24 In every experiment, 2 to 3 independent clones of passage 5 to 20 were analyzed. Results using representative clones, M1-C-8 and M1-C-DA-15, are shown throughout unless otherwise described. Cells were cultured in RPMI 1640 medium (Gibco-BRL, Rockville, MD) supplemented with 10% fetal calf serum (FCS; Intergen, Purchase, NY), 2 mM glutamate, 250 µg/mL Geneticin (Gibco-BRL), streptomycin, and penicillin. Northern blot analysis Total RNAs prepared from cell lines treated with cytokines were analyzed by Northern blotting as described previously.25 Probes used were mouse interferon regulatory factor 1 (IRF-1) complementary DNA (cDNA),24 mouse FcRI cDNA (nucleotides 680-1221), mouse SOCS-1 cDNA (nucleotides 275-650), and mouse SOCS-3 cDNA (nucleotides 440-872). NIH3T3 cells were cultured in Dulbecco modified Eagle medium (Sigma, St Louis, MO) supplemented with 10% FCS. Western blot analysis Cells were treated with 10 ng/mL IL-6 for 10 minutes, 25 ng/mL IFN- for 30 minutes, or 20 ng/mL IL-10 for 20 minutes. Immunoprecipitation and Western blot analysis were done as described previously.24     Results Top Abstract Introduction Materials and methods Results Discussion References IL-6-induced activation of STATs in M1 cells expressing wild-type and a dominant-negative form of PTPC We previously reported that PTPC negatively regulates IL-6- and LIF-induced JAK-STAT signaling when overexpressed in murine M1 cells.24 Specifically, activation of STAT3 is impaired in M1 cells expressing PTPC (M1-C). By contrast, in cells expressing a catalytically inactive form of PTPC, PTPC-DA (M1-C-DA), IL-6 activation of STAT3 was enhanced compared with parent M1 cells and mock-transfected (M1-Neo) cells.24 These results further suggest that PTPC-DA may act as a dominant negative and that endogenous PTPC negatively regulates IL-6-induced JAK-STAT signaling. Studies have identified a SOCS/SSI/CIS family of proteins that inhibits cytokine-induced JAK-STAT signaling(s).7-9 In the SOCS/SSI/CIS family, SOCS-1 and SOCS-3 have been shown to inhibit JAK-STAT signaling induced by IL-6.7,9,26-29 PTPC may function in the up-regulation of protein(s) of the SOCS family. If so, SOCS expression might be observed in M1-C cells even under unstimulated conditions. To address this question, the steady state levels of SOCS-1 and SOCS-3 messenger RNA (mRNA) in M1-stable clones were determined (Figure 1). Expression of SOCS-1 mRNA was not detected in all clones before IL-6 stimulation. IL-6 treatment of M1-Neo cells was accompanied by up-regulation of SOCS-1 mRNA. In M1-C cells, IL-6-mediated up-regulation of SOCS-1 mRNA was reduced. These results are consistent with the previous report that IL-6-induced expression of SOCS-1 mRNA is under the control of STAT3, and IL-6-induced activation of STAT3 is suppressed in M1-C cells.9,24 Additionally, expression of SOCS-3 mRNA was very low in M1 stable clones before and after IL-6 treatment, whereas they were highly expressed in IFN--treated NIH3T3 cells as reported30 (Figure 1). Taken together, these results suggest that negative regulation of cytokine signaling by PTPC is independent of SOCS family proteins. View larger version (47K): [in this window] [in a new window]   Figure 1. Expression of SOCS mRNAs in M1-PTP clones. Total RNA was prepared from M1-stable clones cultured for 4 hours in the absence or presence of 25 ng/mL IL-6 and analyzed for expression of SOCS-1, SOCS-3, and -actin mRNA by Northern blotting. RNA from NIH3T3 cells treated with 25 ng/mL IFN- was also analyzed for SOCS-3 expression as a positive control. To characterize PTPC-mediated regulation of STAT3, a time course of STAT3 phosphorylation/activation induced by IL-6 in M1-C and M1-C-DA cells was undertaken (Figure 2). PTPC and PTPC-DA produced delayed and earlier onset of STAT3 tyrosine phosphorylation following IL-6 stimulation, respectively, suggesting that PTPC may work as a negative regulator at the onset of STAT3 tyrosine phosphorylation. Another PTP SHP-2 has been reported to be involved in negative regulation of gp130 signaling.31-33 Introduction of a point mutation into gp130 that abrogates recruitment of SHP-2 apparently resulted in loss of this negative regulation and in prolonged activation of STAT3 without affecting the onset.31,33 These results suggest different modes of action for the 2 PTPs, PTPC and SHP-2.31,33 View larger version (11K): [in this window] [in a new window]   Figure 2. Effect of PTPC on the onset of IL-6-induced STAT3 tyrosine phosphorylation. M1 stable clones were treated with IL-6 at 10 ng/mL for the times indicated and lysed. Phosphorylated STAT3 was detected by Western blotting with an antibody specific to tyrosine-phosphorylated STAT3 (upper panels). Blots were stripped and reprobed with the anti-STAT3 antibody (lower panels). Although STAT1 was activated by IL-6 to a lesser extent than was STAT3, the activation was gp130-tyrosine phosphorylation-dependent.34,35 Therefore, the effect of PTPC on STAT1 activation was analyzed. STAT1 phosphorylation in M1-Neo cells was undetectable under our experimental conditions. However, in M1-C-DA cells, IL-6 induced tyrosine phosphorylation of STAT1 (Figure 3). This experiment showed that PTPC negatively regulates the activation of STAT1 as well as that of STAT3. View larger version (17K): [in this window] [in a new window]   Figure 3. PTPC inhibits IL-6-induced activation of STAT1. M1 stable clones were treated with IL-6 at 10 ng/mL or with IFN- at 25 ng/mL for 20 minutes and lysed. Phosphorylated STAT1 was detected by Western blotting with an antibody specific to tyrosine-phosphorylated STAT1 (upper panels). Blots were stripped and reprobed with the anti-STAT1 antibody (lower panels). Negative regulation of IL-10 signaling by PTPC Because the JAK-STAT signaling pathway is used by many cytokines, it was important to analyze whether the inhibitory effect of PTPC was specific to signaling induced by IL-6. We therefore investigated the effect of PTPC on IL-10-induced signaling because JAK1, TYK2, and STAT3 are involved in IL-10 signaling as in IL-6-signaling cascade.17,19 First, we determined whether IL-10-Rs were expressed on M1-C and M1-C-DA cells by an IL-10 binding assay. As shown in Figure 4A, these cells bound IL-10 to a similar extent as mock-transfected M1-Neo cells, suggesting similar levels of receptor expression on the surface of all the stable clones. Stable clones were treated with IL-10 for 20 minutes and analyzed for STAT tyrosine phosphorylation. As illustrated in Figure 4B, IL-10 treatment preferentially induced tyrosine phosphorylation of STAT3 in M1-Neo cells. At the same time, STAT1 tyrosine phosphorylation was barely detected (data not shown). In M1-C cells, the level of tyrosine phosphorylation of STAT3 by IL-10 was lower than that seen in M1-Neo cells. View larger version (27K): [in this window] [in a new window]   Figure 4. PTPC inhibits IL-10-induced activation of STAT3. (A) Binding of biotinylated IL-10 to M1 stable clones was analyzed by flow cytometry as described in "Materials and methods." (B) M1 stable clones were treated with IL-10 at 20 ng/mL for 20 minutes and lysed. STAT3 tyrosine phosphorylation was analyzed as in Figure 2. (C) Total RNA was prepared from M1 stable clones cultured for 20 hours in the presence of 20 ng/mL IL-10 and analyzed for expression of FcRI and -actin mRNA by Northern blotting (upper panel). Data represent 1 of 3 independent experiments. It has been shown that IL-10 up-regulates expression of the FcRI gene through STAT3 activation.16,36,37 To determine whether a downstream target of STAT3 induced by IL-10 was also suppressed in M1-C cells, cells were treated with IL-10 and subjected to Northern blot analysis to determine whether the FcRI gene is up-regulated (Figure 4C). A treatment of M1-Neo cells with IL-10 resulted in a slight increase in FcRI mRNA compared with untreated controls (Figure 4C). Significantly, in M1-C cells, IL-10 treatment failed to up-regulate FcRI expression. These results indicate that forced expression of PTPC can inhibit not only IL-6- and LIF-induced signaling but also IL-10-induced JAK-STAT signaling. We also investigated the levels of tyrosine phosphorylation of JAK1 and TYK2 as determined by immunoprecipitation-Western blot analysis (data not shown). However, tyrosine phosphorylation of JAK1 or TYK2 was not detected following IL-10 stimulation of our cell lines. This finding is likely due to the low levels of JAK proteins that are activated in these cells. Effects of PTPC expression on IFN-induced JAK-STAT signaling Subunits of the IL-10-R, IL-10-RI, and CRF2-4 are structurally subgrouped as belonging to the class II cytokine receptor family with IFN-/-R and IFN--R.12,13,38 Given that PTPC negatively regulates IL-10-R-mediated activation of STAT3, we investigated whether PTPC is a common negative regulator of class II receptor-mediated JAK-STAT signaling. To address this issue, M1 stable clones were treated with IFN- and IFN- and analyzed for STAT1 tyrosine phosphorylation. In sharp contrast to IL-10 treatment, PTPC did not block IFN-- and IFN--induced tyrosine phosphorylation of STAT1. Figures 5A and 6A show the time courses of STAT1 tyrosine phosphorylation in M1 stable clones treated with IFN- and IFN-, respectively. In each case, expression of PTPC or PTPC-DA did not affect STAT1 tyrosine phosphorylation, at least up to 3 or 6 hours. In addition to STAT1, tyrosine phosphorylation of JAK1 and STAT3 was not affected by PTPC (Figures 5B and 6B, and data not shown). IRF-1, a downstream effector of IFNs, is induced by IFNs through STAT1-STAT2 heterodimers and STAT1 homodimers.39 As shown in Figures 5C and 6C, expression of IRF-1 mRNA was induced in M1-C cells following IFN- and IFN- treatment, similar to what was observed in M1-Neo cells. SOCS-1 is also reported to be IFN inducible.7,40 Expression of SOCS-1 mRNA by IFNs was similarly induced in all stable clones (Figures 5C and 6C). Taken together, PTPC does not appear to affect IFN--induced JAK-STAT signaling. View larger version (59K): [in this window] [in a new window]   Figure 5. Effect of PTPC on IFN--induced STAT activation. (A) M1 stable clones were treated with IFN- at 1000 U/mL for the times indicated and lysed. STAT1 activation was analyzed as in Figure 3, and (B) STAT3 activation was analyzed as in Figure 2. Cells were treated with IFN- for the times indicated. Total RNA was analyzed for IRF-1 and SOCS-1 expression by Northern blotting. (C) Expression levels of -actin were also estimated. View larger version (39K): [in this window] [in a new window]   Figure 6. Effect of PTPC on IFN--induced STAT activation. (A) M1 stable clones were treated with IFN- at 25 ng/mL for the times indicated and lysed. STAT1 activation was analyzed as in Figure 3, and (B) STAT3 activation was analyzed as in Figure 2B. Cells were treated with IFN- for the times indicated. Total RNA was analyzed for IRF-1 and SOCS-1 mRNA by Northern blotting. (C) The expression levels of -actin were also estimated.     Discussion Top Abstract Introduction Materials and methods Results Discussion References We and others have reported that expression of PTPC is up-regulated during macrophage differentiation and/or activation. As noted previously, PTPC inhibited IL-10-induced STAT3 activation but not IFN--induced STAT1 activation. It is well established that IFN- and IL-10 have pleiotrophic effects on regulation of macrophage activation and de-activation, respectively.10,41,42 In this context, PTPC might play important roles in facilitating activation of macrophages and/or in maintaining activated states by selective down-regulation of the de-activating IL-10 signal. Because PTPC is expressed not only in myeloid/monocytic lineages but also in lymphocytes (K.N. and N.T., unpublished results, March 2001), it would be of great interest and importance to determine whether PTPC plays negative regulatory roles in cytokine signaling in lymphocytes. In summary, results in this study reveal an inhibitory effect of PTPC on STAT activation induced by IL-10 as well as by IL-6. Negative regulation by PTPC does not involve SOCS family proteins (at least not SOCS-1 and -3) and may have a different mode of action from SHP-2. In contrast, PTPC appears not to interfere with IFN-- and IFN--induced JAK-STAT signaling. Our results indicate that PTPC inhibition of JAK-STAT activation is not specified by particular JAKs or STATs. Instead, PTPC-mediated suppression is selective for certain JAK-STAT signaling pathways through corresponding cytokine receptors such as gp130 and IL-10-R. Identification of target(s) of PTPC-mediated suppression will enable us to fully understand the molecular basis for regulation of cytokine signaling.     Acknowledgments We thank Dr T. Abo for murine IFN- and Dr T. Minagawa for murine IFN-. Additionally, we thank Dr N. Urushibara for help with some of the experiments, and Y. Saito and E. Yoshida for secretarial assistance.     Footnotes Submitted March 30, 2001; accepted July 17, 2001. Supported in part by Grant-in-Aids for Scientific Research provided by the Japan Society for the Promotion of Science and a Grant-in-Aid for Scientific Research on Priority Areas provided by the Ministry of Education, Culture, Sports, Science and Technology of Japan. The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734. Reprints: Kunimi Kikuchi, Division of Biochemical Oncology and Immunology, Institute for Genetic Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-Ku, Sapporo 060-0815, Japan; e-mail: kikuchi{at}imm.hokudai.ac.jp.     References Top Abstract Introduction Materials and methods Results Discussion References 1. Darnell JJ, Kerr IM, Stark GR. Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science. 1994;264:1415-1421[Abstract/Free Full Text]. 2. Ihle JN, Witthuhn BA, Quelle FW, Yamamoto K, Silvennoinen O. Signaling through the hematopoietic cytokine receptors. Annu Rev Immunol. 1995;13:369-398[CrossRef][Medline] [Order article via Infotrieve]. 3. Darnell JJ. STATs and gene regulation. Science. 1997;277:1630-1635[Abstract/Free Full Text]. 4. Leonard WJ, O'Shea JJ. Jaks and STATs: biological implications. Annu Rev Immunol. 1998;16:293-322[CrossRef][Medline] [Order article via Infotrieve]. 5. Takeda K, Akira S. 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The transcription factor IRF-1 and its family members in the regulation of host defense. Cold Spring Harb Symp Quant Biol. 2000;64:465-472. 40. Gil MP, Bohn E, O'Guin AK, et al. Biologic consequences of Stat1-independent IFN signaling. Proc Natl Acad Sci U S A. 2001;98:6680-6685[Abstract/Free Full Text]. 41. Stark GR, Kerr IM, Williams BR, Silverman RH, Schreiber RD. How cells respond to interferons. Annu Rev Biochem. 1998;67:227-264[CrossRef][Medline] [Order article via Infotrieve]. 42. Takeda K, Clausen BE, Kaisho T, et al. Enhanced Th1 activity and development of chronic enterocolitis in mice devoid of Stat3 in macrophages and neutrophils. Immunity. 1999;10:39-49[CrossRef][Medline] [Order article via Infotrieve]. © 2001 by The American Society of Hematology.   CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: T. Tougan, H. Onda, D. Okuzaki, S. Kobayashi, H. Hashimoto, and H. 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