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Interleukin-6 Inhibits Transforming Growth Factor-β-induced Apoptosis through the Phosphatidylinositol 3-Kinase/Akt and Signal Transducers and Activators of Transcription 3 Pathways*

Open AccessPublished:August 13, 1999DOI:https://doi.org/10.1074/jbc.274.33.23013
      The multifunctional cytokine interleukin-6 (IL-6) regulates growth and differentiation of many cell types and induces production of acute-phase proteins in hepatocytes. Here we report that IL-6 protects hepatoma cells from apoptosis induced by transforming growth factor-β (TGF-β), a well known apoptotic inducer in liver cells. Addition of IL-6 blocked TGF-β-induced activation of caspase-3 while showing no effect on the induction of plasminogen activator inhibitor-1 and p15INK4B genes, indicating that IL-6 interferes with only a subset of TGF-β activities. To further elucidate the mechanism of this anti-apoptotic effect of IL-6, we investigated which signaling pathway transduced by IL-6 is responsible for this effect. IL-6 stimulation of hepatoma cells induced a rapid tyrosine phosphorylation of the p85 subunit of phosphatidylinositol 3-kinase (PI 3-kinase) and its kinase activity followed by the activation of Akt. Inhibition of PI 3-kinase by wortmannin or LY294002 abolished the protection of IL-6 against TGF-β-induced apoptosis. A dominant-negative Akt also abrogated this anti-apoptotic effect. Dominant-negative inhibition of STAT3, however, only weakly attenuated the IL-6-induced protection. Finally, inhibition of both STAT3 and PI 3-kinase by treating cells overexpressing the dominant-negative STAT3 with LY294002 completely blocked IL-6-induced survival signal. Thus, concomitant activation of the PI 3-kinase/Akt and the STAT3 pathways mediates the anti-apoptotic effect of IL-6 against TGF-β, with the former likely playing a major role in this anti-apoptosis.
      TGF-β
      transforming growth factor-β
      PI 3-kinase
      phosphatidylinositol 3-kinase
      IL-6
      interleukin-6
      JAK
      Janus kinase
      STAT
      signal transducer and activator of transcription
      PAI-1
      plasminogen activator inhibitor-1
      SH2
      Src homology domain 2
      MAP
      mitogen-activated protein
      PAGE
      polyacrylamide gel electrophoresis
      ELISA
      enzyme-linked immunosorbent assay
      A balance between cell proliferation and apoptosis is critical for tissue homeostasis. Maintenance of the size of liver is a notable example of homeostasis which is heavily regulated by many growth factors and cytokines (
      • Michalopoulos G.K.
      • DeFrances M.C.
      ). Among these factors, transforming growth factor-β (TGF-β)1 is a potent inducer of apoptosis in hepatocytes and several hepatoma cell lines, as well as in regressing liver in vivo (
      • Fan G.
      • Ma X.
      • Kren B.
      • Steer C.J.
      ,
      • Fukuda K.
      • Kojiro M.
      • Chiu J.F.
      ,
      • Lin J.K.
      • Chou C.K.
      ,
      • Oberhammer F.A.
      • Pavelka M.
      • Sharma S.
      • Tiefenbacher R.
      • Purchio A.F.
      • Bursch W.
      • Schulte-Hermann R.
      ,
      • S‡nchez A.
      • Çlvarez A.M.
      • Benito M.
      • Fabregat I.
      ). TGF-β also inhibits liver cell proliferation in vitro (
      • Inagaki M.
      • Moustakas A.
      • Lin H.Y.
      • Carr B.I.
      ) and plays a crucial role in terminating liver regeneration after partial hepatectomy (
      • Michalopoulos G.K.
      • DeFrances M.C.
      ). TGF-β exerts its biological effects through the action of two types of transmembrane serine/threonine kinase receptors. These receptors subsequently propagate the signal by phosphorylating the intracellular targets, Smads. Phosphorylated Smad2 or Smad3 can form a stable complex with Smad4, which then translocates to the nucleus to regulate transcriptional responses to TGF-β (
      • Heldin C.-H.
      • Miyazono K.
      • ten Dijke P.
      ,
      • Massague J.
      • Hata A.
      • Liu F.
      ,
      • Zhang Y.
      • Musci T.
      • Derynck R.
      ). Although the signal transduction pathway of TGF-β has been well studied, mechanism of its apoptotic effect is still not fully characterized. Nevertheless, induction of oxidative stress (
      • S‡nchez A.
      • Çlvarez A.M.
      • Benito M.
      • Fabregat I.
      ), activation of caspase-3 (
      • Fukuda K.
      • Kojiro M.
      • Chiu J.F.
      ,
      • Chen R.-H.
      • Chang T.Y.
      ), and inhibition of pRb expression (
      • Fan G.
      • Ma X.
      • Kren B.
      • Steer C.J.
      ) have been implicated in mediating TGF-β-induced apoptosis.
      TGF-β-induced apoptosis in liver cells is blocked by growth factors such as insulin and insulin-like growth factor-1 as well as by elevated expression of insulin receptor substrate-1 (
      • Tanaka S.
      • Wands J.R.
      ). Our recent studies have revealed that the phosphatidylinositol 3-kinase (PI 3-kinase) and its downstream target, Akt, are responsible for the anti-apoptotic activity of insulin against TGF-β (
      • Chen R.-H.
      • Su Y.-H.
      • Chuang R.L.C.
      • Chang T.-Y.
      ). PI 3-kinase was reported to suppress apoptotic cell death induced by a variety of stimuli (
      • Ahmed N.N.
      • Grimes H.L.
      • Bellacosa A.
      • Chan T.O.
      • Tsichlis P.N.
      ,
      • Dudek H.
      • Datta S.R.
      • Franke T.F.
      • Bimbaum M.J.
      • Yao R.
      • Cooper G.M.
      • Segel R.S.
      • Kaplan D.R.
      • Greenberg M.E.
      ,
      • Kauffmann-Zeh A.
      • Rodriguez-Vicana P.
      • Ulrich E.
      • Gilbert C.
      • Coffer P.
      • Downward J.
      • Evan G.
      ,
      • Kennedy S.G.
      • Wagner A.J.
      • Conzen S.D.
      • Jordan J.
      • Bellacosa A.
      • Tsichlis P.N.
      • Hay N.
      ,
      • Khwaja A.
      • Rodriguez-Vicana P.
      • Wennstrom S.
      • Warne P.H.
      • Downward J.
      ,
      • Kulik G.
      • Klippel A.
      • Weber M.J.
      ). PI 3-kinase elicits this anti-apoptotic activity through the action of the serine/threonine kinase, Akt. Recent studies have demonstrated that activated Akt can phosphorylate the proapoptotic protein BAD (
      • Datta S.R.
      • Dudek H.
      • Tao X.
      • Masters S.
      • Fu H.
      • Gotoh Y.
      • Greenberg M.E.
      ,
      • del Peso L.
      • Gonzáles-Garcia M.
      • Page C.
      • Herrera R.
      • Nunez G.
      ). This phosphorylation allows for BAD association with 14-3-3 and dissociation from BCL-XL, which is then free to resume its function as a suppressor of apoptosis (
      • Zha J.
      • Harada H.
      • Yang E.
      • Jockel J.
      • Korsmeyer S.J.
      ).
      Interleukin-6 (IL-6) is a mutilfunctional cytokine acting in the immune system, hepatocytes, and neuronal cells (
      • Van Snick J.
      ,
      • Hirano T.
      ). In the liver, IL-6 induces synthesis of acute-phase proteins and plays central roles in preventing acute hepatitis and initiating liver regeneration (
      • Mizuhara H.
      • O'Neill E.
      • Seki N.
      • Ogawa T.
      • Kusunoki C.
      • Otsuka K.
      • Satoh S.
      • Niwa M.
      • Senoh H.
      • Fujiwara H.
      ,
      • Cressman D.
      • Greenbaum L.
      • DeAngelis R.
      • Ciliberto G.
      • Furth E.
      • Poli V.
      • Taub R.
      ). Mice with targeted disruption of the IL-6 gene have impaired liver regeneration characterized by liver necrosis and failure (
      • Cressman D.
      • Greenbaum L.
      • DeAngelis R.
      • Ciliberto G.
      • Furth E.
      • Poli V.
      • Taub R.
      ). The signaling mechanism of IL-6 in hepatocytes is, however, not fully understood. In hematopoietic cells, binding IL-6 to the α subunit of its receptor triggers the recruitment of gp130, subsequently leading to the activation of the gp130-associated Janus kinases (JAKs) (
      • Murakami M.
      • Hibi M.
      • Nakagawa N.
      • Yasukawa K.
      • Yamanishi K.
      • Taga T.
      • Kishimoto T.
      ,
      • Lutticken C.
      • Wegenka U.M.
      • Yuan J.
      • Buschmann J.
      • Schindler C.
      • Ziemiecki A.
      • Harpur A.G.
      • Wilks A.F.
      • Yasukawa K.
      • Taga T.
      • Kishimoto T.
      • Barbirri G.
      • Pellegrini S.
      • Sendtner M.
      • Heinrich P.C.
      • Horn F.
      ,
      • Narazaki M.
      • Witthuhn B.A.
      • Yoshida K.
      • Silvennoinen O.
      • Yasukawa K.
      • Ihle J.N.
      • Kishimoto T.
      • Taga T.
      ). JAKs phosphorylate gp130 on several tyrosine residues and these phosphotyrosines recruit various SH2 domain-containing proteins, such as STAT3 and SHP-2 (
      • Akira S.
      • Nishio Y.
      • Inoue M.
      • Wang X.J.
      • Wei S.
      • Matsusaka T.
      • Yoshida K.
      • Sudo T.
      • Naruto M.
      • Kishimoto T.
      ,
      • Boulton T.G.
      • Stahl N.
      • Yancopoulos G.D.
      ,
      • Sadowski H.B.
      • Shuai K.
      • Darnell Jr., J.E.
      • Gilman M.Z.
      ). SHP-2 links cytokine receptor to the Ras/MAP kinase pathway and is essential for mitogenic activity, whereas STAT3 can induce BCL-2 and is involved in anti-apoptosis (
      • Fukada T.
      • Hibi M.
      • Yamanaka Y.
      • Takahashi-Tezuka M.
      • Fujitani Y.
      • Yamaguchi T.
      • Nakajima K.
      • Hirano T.
      ). In addition to JAK/STAT and Ras/MAP kinase pathways, IL-6 was recently shown to activate PI 3-kinase in prostate cancer cells (
      • Qiu Y.
      • Robinson D.
      • Pretlow T.G.
      • Kung H.-J.
      ). Whether IL-6 in liver cells activates these pathways remains to be investigated.
      In the liver, IL-6 acts as a hepatoprotecting and/or mitogenic factor, whereas TGF-β elicits an apoptotic and/or growth-arresting effect. In this study, we elucidate a cross-talk between signaling pathways induced by these two factors in liver cells. Our results indicate that IL-6 suppressed TGF-β-induced apoptotic death of hepatoma cells in a dose-dependent manner. IL-6 inhibited TGF-β-induced activation of caspase-3 but did not affect its induction of an extracellular matrix protein and a cell cycle inhibitor, suggesting that IL-6 signaling blocks only the apoptotic signaling of TGF-β. Furthermore, we demonstrate that the concomitant activation of the PI 3-kinase/Akt and the STAT3 signaling pathways mediates the anti-apoptotic effect of IL-6 against TGF-β.

      DISCUSSION

      IL-6 is a pleiotropic cytokine capable not only of inducing growth and differentiation in many cell types but also of stimulating acute-phase protein synthesis in liver cells (
      • Van Snick J.
      ,
      • Hirano T.
      ). However, the anti-apoptotic effect of IL-6 has not been well documented. In this study, we demonstrated that IL-6 suppressed TGF-β-induced apoptotic death of hepatoma cells in a dose-dependent manner. The anti-apoptotic effect of IL-6 correlated with its inhibition of TGF-β-induced activation of caspase-3. IL-6 stimulation, however, did not alter the effect of TGF-β on the induction of PAI-1 and p15INK4B genes. Our results suggest that IL-6 interferes with only a subset of TGF-β signaling without affecting general TGF-β signaling.
      This study provides several insights into the anti-apoptotic mechanism of IL-6. The PI 3-kinase/Akt and the JAK/STAT3 pathways are both activated by IL-6 and function cooperatively to achieve the maximal anti-apoptotic effect of IL-6 against TGF-β. Previous investigations have indicated that the PI 3-kinase/Akt is involved in preventing apoptosis induced by various growth factors in many different cell types (
      • Ahmed N.N.
      • Grimes H.L.
      • Bellacosa A.
      • Chan T.O.
      • Tsichlis P.N.
      ,
      • Dudek H.
      • Datta S.R.
      • Franke T.F.
      • Bimbaum M.J.
      • Yao R.
      • Cooper G.M.
      • Segel R.S.
      • Kaplan D.R.
      • Greenberg M.E.
      ,
      • Kauffmann-Zeh A.
      • Rodriguez-Vicana P.
      • Ulrich E.
      • Gilbert C.
      • Coffer P.
      • Downward J.
      • Evan G.
      ,
      • Kennedy S.G.
      • Wagner A.J.
      • Conzen S.D.
      • Jordan J.
      • Bellacosa A.
      • Tsichlis P.N.
      • Hay N.
      ,
      • Khwaja A.
      • Rodriguez-Vicana P.
      • Wennstrom S.
      • Warne P.H.
      • Downward J.
      ,
      • Kulik G.
      • Klippel A.
      • Weber M.J.
      ,
      • Datta S.R.
      • Dudek H.
      • Tao X.
      • Masters S.
      • Fu H.
      • Gotoh Y.
      • Greenberg M.E.
      ,
      • del Peso L.
      • Gonzáles-Garcia M.
      • Page C.
      • Herrera R.
      • Nunez G.
      ), whereas STAT3 is a critical mediator of the anti-apoptotic effect of oncostatin M in osteosarcoma cells (
      • Bellido T.
      • O'Brien C.A.
      • Roberson P.K.
      • Manolagas S.C.
      ) and the survival signals transduced by gp130 in B cells (
      • Fukada T.
      • Hibi M.
      • Yamanaka Y.
      • Takahashi-Tezuka M.
      • Fujitani Y.
      • Yamaguchi T.
      • Nakajima K.
      • Hirano T.
      ). The anti-apoptotic mechanism of PI 3-kinase/Akt is at least partially attributed to phosphorylation of the BCL-2 family member BAD by Akt (
      • Datta S.R.
      • Dudek H.
      • Tao X.
      • Masters S.
      • Fu H.
      • Gotoh Y.
      • Greenberg M.E.
      ,
      • del Peso L.
      • Gonzáles-Garcia M.
      • Page C.
      • Herrera R.
      • Nunez G.
      ). The phosphorylated BAD is then associated with 14-3-3, which sequesters BAD from BCL-XL, thereby promoting cell survival (
      • Zha J.
      • Harada H.
      • Yang E.
      • Jockel J.
      • Korsmeyer S.J.
      ). Regulating the BCL-2 family member is also considered as one of the anti-apoptotic mechanisms of STAT3, which was reported to be capable of inducing BCL-2 in pro-B cells (
      • Fukada T.
      • Hibi M.
      • Yamanaka Y.
      • Takahashi-Tezuka M.
      • Fujitani Y.
      • Yamaguchi T.
      • Nakajima K.
      • Hirano T.
      ). Thus, both anti-apoptotic signaling pathways transduced by IL-6 are likely to converge to BCL-2 family members, which could act upstream of caspase-3 (
      • Cryns V.
      • Yuan J.
      ,
      • Rao L.
      • White E.
      ). This is consistent with our finding that IL-6 blocked the TGF-β-induced activation of caspase-3. In addition to induction of BCL-2, STAT3 can directly up-regulate the transcription of p21, which is implicated in the anti-apoptosis (
      • Bellido T.
      • O'Brien C.A.
      • Roberson P.K.
      • Manolagas S.C.
      ). In our system, an increased expression of p21 upon IL-6 stimulation was also observed (data not shown). Whether p21 and BCL-2 are induced independently by STAT3 and exactly how p21 promotes survival remain to be investigated.
      IL-6 was reported to protect multiple myeloma plasma cells from anti-Fas- and dexamethasone-induced apoptosis (
      • Xu F.-h.
      • Sharma S.
      • Garner A.
      • Tu Y.
      • Raitano A.
      • Sawyers C.
      • Lichtenstein A.
      ). Inhibition of JNK/SAPK pathway is involved in IL-6-induced protection against anti-Fas but not dexamethasone. These results support a hypothesis that multiple mechanisms are involved in the IL-6-induced anti-apoptosis. However, blockage of JNK/SAPK pathway is unlikely to account for the mechanism by which IL-6 suppresses TGF-β-induced apoptosis, since TGF-β failed to induce JNK/SAPK activity in Hep3B cells (data not shown). Thus, distinct signaling pathways could mediate IL-6-induced protection from apoptosis induced by different stimuli.
      Previous studies demonstrated that dominant-negative inhibition of STAT3 activity completely abolishes gp130-mediated survival signal in a pro-B cell line (
      • Fukada T.
      • Hibi M.
      • Yamanaka Y.
      • Takahashi-Tezuka M.
      • Fujitani Y.
      • Yamaguchi T.
      • Nakajima K.
      • Hirano T.
      ). In the case of Hep3B cells, however, the same dominant-negative mutants only partially blocked the anti-apoptotic effect of IL-6 against TGF-β. Interestingly, in mouse leukemia M1 cells, STAT3 is involved in the differentiation and growth arrest but not required for the anti-apoptotic signal (
      • Nakajima K.
      • Yamanaka Y.
      • Nakae K.
      • Kojima H.
      • Ichiba M.
      • Kiuchi N.
      • Kitaoka T.
      • Fukada T.
      • Hibi M.
      • Hirano T.
      ,
      • Yamanaka Y.
      • Nakajima K.
      • Fukada T.
      • Hibi M.
      • Hirano T.
      ). These findings highlight the significance of cellular context in determining the biological functions of STAT3. STAT3 may induce the expression of a distinct set of genes depending on cell type involved. Another determinant of the biological consequences of STAT3 activation is likely to be the concomitant activation of other STAT family members and/or other signaling pathways, such as the PI 3-kinase/Akt pathway, upon ligand binding to the cytokine receptors.
      A recent investigation indicated that IL-6 treatment of prostate cancer cell line LNCaP induces an increase in tyrosine phosphorylation of the p85 subunit of PI 3-kinase and its kinase activity (
      • Qiu Y.
      • Robinson D.
      • Pretlow T.G.
      • Kung H.-J.
      ). Accordingly, we observed a rapid induction of p85 tyrosine phosphorylation and PI 3-kinase activity by IL-6 in Hep3B cells. In addition, two specific inhibitors of PI 3-kinase, wortmannin and LY294002, blocked the anti-apoptotic effect of IL-6, implying the activation of PI 3-kinase by IL-6. Furthermore, we demonstrated for the first time that the serine/threonine kinase Akt is activated upon IL-6 treatment. A similar induction of PI 3-kinase and Akt activities was found in cardiac myocytes stimulated with leukemia inhibitory factor, a cytokine transducing signal via gp130 (
      • Oh H.
      • Fujio Y.
      • Kunisada K.
      • Hirota H.
      • Matsui H.
      • Kishimoto T.
      • Yamauchi-takihara K.
      ). Thus, in addition to JAK/STAT and Ras/MAP kinase pathways, the PI 3-kinase/Akt could be an important signaling pathway activated by various cytokines. The mechanism of IL-6-induced activation of PI 3-kinase remains unclear, although JAK can bind PI 3-kinase upon activation of gp130 (
      • Oh H.
      • Fujio Y.
      • Kunisada K.
      • Hirota H.
      • Matsui H.
      • Kishimoto T.
      • Yamauchi-takihara K.
      ).
      In the liver, IL-6 plays a crucial role in anti-inflammatory responses to prevent liver injury (
      • Mizuhara H.
      • O'Neill E.
      • Seki N.
      • Ogawa T.
      • Kusunoki C.
      • Otsuka K.
      • Satoh S.
      • Niwa M.
      • Senoh H.
      • Fujiwara H.
      ,
      • Camargo Jr., C.A.
      • Madden J.F.
      • Gao W.
      • Selvan R.S.
      • Clavien P.-A.
      ) and is a key growth factor to initiate liver regeneration (
      • Michalopoulos G.K.
      • DeFrances M.C.
      ,
      • Cressman D.
      • Greenbaum L.
      • DeAngelis R.
      • Ciliberto G.
      • Furth E.
      • Poli V.
      • Taub R.
      ). This study demonstrates another important activity of IL-6 in the liver, namely, anti-apoptosis. We propose that the ability of IL-6 to suppress apoptosis induced by TGF-β could be physiologically important. TGF-β is thought to be a terminator of liver regeneration through its growth-inhibitory and apoptotic effects (
      • Michalopoulos G.K.
      • DeFrances M.C.
      ). However, the mRNA of TGF-β is induced at an initiation stage of liver regeneration (
      • Braun L.
      • Mead J.E.
      • Panzica M.
      • Mikumo R.
      • Bell G.I.
      ), indicating that hepatocytes can proceed with regeneration despite the increase in the concentrations of TGF-β. Accordingly, hepatocytes isolated from actively regenerating liver are resistant to TGF-β (
      • Houck K.A.
      • Michalopoulos G.K.
      ). This raises the possibility that the effect of TGF-β is blocked by other growth factors and/or cytokines as part of their regeneration-promoting effects. IL-6 is a logical candidate of these factors, because the timing of its induction correlates with the resistance of hepatocytes to TGF-β (
      • Rai R.M.
      • Yang S.Q.
      • McClain C.
      • Karp C.L.
      • Klein S.
      • Diehl A.M.
      ). Additional studies would be required to further define the physiological roles of the anti-apoptotic activity of IL-6 against TGF-β in liver cells.

      Acknowledgments

      We thank Dr. H.-F. Yang-Yen for helpful instructions on PI 3-kinase assay, Drs. R. Derynck and X.-F. Wang for providing reporter constructs, Dr. T. Hirano for the dominant-negative STAT3, and Rachel L. Chuang for excellent technical assistance. We also acknowledge Dr. C.-H. Wu for critical reading of the manuscript.

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