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257.Full.Pdf TNF-α Induces Tyrosine Phosphorylation and Recruitment of the Src Homology Protein-Tyrosine Phosphatase 2 to the gp130 Signal-Transducing Subunit of the IL-6 This information is current as Receptor Complex of October 1, 2021. Johannes G. Bode, Jens Schweigart, Jan Kehrmann, Christian Ehlting, Fred Schaper, Peter C. Heinrich and Dieter Häussinger J Immunol 2003; 171:257-266; ; Downloaded from doi: 10.4049/jimmunol.171.1.257 http://www.jimmunol.org/content/171/1/257 References This article cites 54 articles, 32 of which you can access for free at: http://www.jimmunol.org/ http://www.jimmunol.org/content/171/1/257.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on October 1, 2021 • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2003 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology TNF-␣ Induces Tyrosine Phosphorylation and Recruitment of the Src Homology Protein-Tyrosine Phosphatase 2 to the gp130 Signal-Transducing Subunit of the IL-6 Receptor Complex1 Johannes G. Bode,2* Jens Schweigart,* Jan Kehrmann,* Christian Ehlting,* Fred Schaper,† Peter C. Heinrich,† and Dieter Ha¨ussinger* Recently, it has been demonstrated that TNF-␣ and LPS induce the expression of suppressor of cytokine signaling 3 (SOCS3) and inhibit IL-6-induced STAT3 activation in macrophages. Inhibitor studies suggested that both induction of SOCS3 and inhibition of IL-6-induced STAT3 activation depend on the activation of p38 mitogen-activated protein kinase. Since recruitment of the tyrosine phosphatase Src homology protein tyrosine phosphatase 2 (SHP2) to the signal-transducing receptor subunit gp130 attenuates IL-6-mediated STAT-activation, we were interested in whether TNF-␣ also induces the association of SHP2 to the gp130 receptor subunit. In this study we demonstrate that stimulation of macrophages and fibroblast cell lines with TNF-␣ causes Downloaded from the recruitment of SHP2 to the gp130 signal-transducing subunit and leads to tyrosine phosphorylation of SHP2 and gp130. In this context the cytoplasmic SHP2/SOCS3 recruitment site of gp130 tyrosine 759 is shown to be important for the inhibitory effects of TNF-␣, since mutation of this residue completely restores IL-6-stimulated activation of STAT3 and, consequently, of a STAT3- dependent promoter. In this respect murine fibroblasts lacking exon 3 of SHP2 are not sensitive to TNF-␣, indicating that functional SHP2 and its recruitment to gp130 are key events in inhibition of IL-6-dependent STAT activation by TNF-␣. Fur- thermore, activation of p38 mitogen-activated protein kinase is shown to be essential for the inhibitory effect of TNF-␣ on IL-6 http://www.jimmunol.org/ signaling and TNF-␣-dependent recruitment of SHP2 to gp130. The Journal of Immunology, 2003, 170: 257–266. he inflammatory cascade underlying the immune response macrophages (5–7), astrocytes (9), and fibroblasts (10) IL-6 has of an organism toward pathogens is largely controlled by suppressive effects on their inflammatory response and represses T the actions of different mediators released under inflam- the expression of IL-12, IFN-␥, IL-1␤, TNF-␣, adhesion mole- matory conditions. Upon activation, blood monocytes and tissue cules, and proteases both in vitro and in vivo (5–10). In line with macrophages release a set of primary inflammatory mediators, this, IL-6 is able to induce the expression of IL-1␤R antagonist and ␤ ␣ ␤ ␣ such as IL-1 and TNF- , thereby inducing the synthesis and se- soluble TNF receptor p55, antagonizing IL-1 and TNF- activ- by guest on October 1, 2021 cretion of several secondary cytokines and chemokines, such as ities, respectively (11, 12). IL-6 and IL-8, by macrophages, monocytes, and local stromal Thus, IL-6 mediates both pro- and anti-inflammatory effects. cells. Recruitment of other immune effector cells by chemotaxis IL-6 is expressed throughout every stage of the inflammatory re- then rapidly augments the local inflammatory response to coun- sponse, and at least during the onset of inflammation several of its teract the inflammatory stimulus and to remove cellular debris as- anti-inflammatory properties would be inconvenient (1–5). There- sociated with tissue damage (reviewed in Refs. 1–5). fore, it is mandatory that molecular mechanisms modulating IL-6 In this context IL-6 has been considered a proinflammatory cy- action exist. tokine, since its expression is elevated in inflammatory diseases IL-6 mediates its biological activities through a receptor com- and is induced by inflammatory stimuli, such as IL-1␤ and TNF-␣ plex composed of the specific receptor subunit gp80 and a dimer of (1, 2, 5). Many of its proinflammatory and immune properties are the signal-transducing receptor subunit gp130 (2). After ligand due to the activation of B cells to produce Abs due to the stimu- binding and dimerization of gp130, tyrosine kinase of the Janus lation of T cells and the induction of chemokine and adhesion family (Jak),3 Jak1, Jak2, and Tyk2, constitutively associated with molecule expression in endothelial cells (2, 5–8). However, on gp130, becomes activated by autophosphorylation. The gp130 sub- sequently tyrosine-phosphorylated on its cytoplasmic tail recruits transcription factors of the STAT family (13, 14) and Src homol- *Klinik fu¨r Gastroenterologie, Hepatologie und Infektiologie, Medizinische Klinik der Heinrich Heine Universita¨t, Düsseldorf, Germany; and †Institut fu¨r Biochemie, ogy protein tyrosine phosphatase 2 (SHP2) (15) via specific phos- Universita¨tsklinikum der Rheinisch-Westfa¨lischen Technischen Hochschule Aachen, photyrosine-SH2 domain interactions involving the tyrosine 759 of Aachen, Germany the gp130 receptor (16, 17). In turn, these components also become Received for publication September 19, 2002. Accepted for publication April tyrosine phosphorylated. Activated STATs homo- or heterodimer- 18, 2003. ize (18), translocate to the nucleus, and bind to enhancer elements The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance of target genes (19). with 18 U.S.C. Section 1734 solely to indicate this fact. 1 This work was supported by the Deutsche Forschungsgemeinschaft (Bonn, Ger- many) through the collaborative research center SFB 575 Experimentelle Hepatologie (Düsseldorf, Germany). 3 Abbreviations used in this paper: Jak, Janus kinase; Erk, extracellular signal-regu- 2 Address correspondence and reprint requests to Dr. Johannes G. Bode, Medizinische lated kinase; Epo, erythropoietin; IRF, IFN-regulatory factor; MAPK, mitogen-acti- Universita¨tsklinik, Klinik fu¨r Gastroenterologie, Hepatologie und Infektiologie, Hei- vated protein kinase; PIAS, protein inhibitor of activated STATs; SHP, SH2-contain- nrich Heine Universita¨t, Moorenstrasse 5, D-40225 Düsseldorf, Germany. E-mail ing protein tyrosine phosphatase; SOCS, suppressor of cytokine signaling; wt, wild address: [email protected] type. Copyright © 2003 by The American Association of Immunologists, Inc. 0022-1767/03/$02.00 258 TNF-␣-INDUCED PREASSOCIATION OF SHP2 AND gp130 The Jak/STAT signal transduction pathway is under negative anti-phosphotyrosine mouse mAb 4G10 (Upstate Biotechnology, Lake control by several different mechanisms. The presence of a nuclear Placid, NY) was used. phosphatase leading to dephosphorylation and inactivation of ac- Cultivation and stimulation of cells tivated STATs in the nucleus has been proposed by Haspel et al. RAW 264.7 cells were cultivated in DMEM (1000 mg of glucose/liter) (20). On the other hand, Kim and Maniatis (21) demonstrated a with Glutamax supplemented with 10% heat-inactivated FCS, streptomy- proteasome-dependent loss of activated STAT1 in the nucleus. Re- cin (100 mg/liter), and penicillin (60 mg/L). NIH-3T3 cells were grown in cently, another group of inhibitors of the Jak/STAT pathway has DMEM (4500 mg of glucose/L) with Glutamax supplemented with 10% been described: STAT-binding proteins, known as protein inhibi- heat-inactivated FCS, streptomycin (100 mg/L), and penicillin (60 mg/L). tors of activated STATs (PIAS) (22, 23). Although the PIAS do 3T3 embryonal fibroblasts were from SHP2 wild-type mice (SHP2-wt) or SHP2 exon 3-deficient mice (SHP2-mut) and were grown in DMEM (4500 not contain phosphotyrosine binding domains such as SH2 or pro- mg of glucose/L) with Glutamax, 10% FCS, 100 mg/L streptomycin, and tein tyrosine binding domains, they associate with activated, ty- 60 mg/L penicillin (35). rosine-phosphorylated STATs, leading to a loss of STAT-DNA All experiments, except those for the analysis of protein phosphoryla- binding activity. The mechanism and regulation of this highly spe- tion, were performed in the respective culture medium supplemented with 10% FCS. For the analysis of STAT3 and Erk1/2 phosphorylation, medium cific
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