Activation of the Pro-survival Phosphatidylinositol 3-Kinase/AKT Pathway by Transforming Growth Factor-β1 in Mesenchymal Cells Is Mediated by p38 MAPK-dependent Induction of an Autocrine Growth Factor

Transforming growth factor-β1 (TGF-β1) is a multifunctional cytokine involved in differentiation, growth, and survival of mesenchymal cells while inhibiting growth/survival of most other cell types. The mechanism (s) of pro-survival signaling by TGF-β1 in mesenchymal cells is unclear. In this report, we demonstrate that TGF-β1 protects against serum deprivation-induced apoptosis of mesenchymal cells isolated from patients with acute lung injury and of normal human fetal lung fibroblasts (IMR-90). TGF-β receptor (s) -activated signaling in these cells involves rapid activation of the Smad and p38 MAPK pathways within minutes of TGF-β1 treatment followed by a more delayed activation of the pro-survival phosphatidylinositol 3-kinase-protein kinase B (PKB) /Akt pathway. Pharmacological inhibition of p38 MAPK with SB203580 or expression of a p38 kinase-deficient mutant protein inhibits TGF-β1-induced PKB/Akt phosphorylation. Conditioned medium from TGF-β1-treated cells rapidly induces PKB/Akt activation in an SB203580- and suramin-sensitive manner, suggesting p38 MAPK-dependent production of a secreted growth factor that activates this pro-survival pathway by an autocrine/paracrine mechanism. Inhibition of the phosphatidylinositol 3-kinase-PKB/Akt pathway blocks TGF-β1-induced resistance to apoptosis. These results demonstrate the activation of a novel TGF-β1-activated pro-survival/anti-apoptotic signaling pathway in mesenchymal cells/fibroblasts that may explain cell-specific actions of TGF-β1 and provide mechanistic insights into its pro-fibrotic and tumor-promoting effects. Transforming growth factor-β1 (TGF-β1) is a multifunctional cytokine involved in differentiation, growth, and survival of mesenchymal cells while inhibiting growth/survival of most other cell types. The mechanism (s) of pro-survival signaling by TGF-β1 in mesenchymal cells is unclear. In this report, we demonstrate that TGF-β1 protects against serum deprivation-induced apoptosis of mesenchymal cells isolated from patients with acute lung injury and of normal human fetal lung fibroblasts (IMR-90). TGF-β receptor (s) -activated signaling in these cells involves rapid activation of the Smad and p38 MAPK pathways within minutes of TGF-β1 treatment followed by a more delayed activation of the pro-survival phosphatidylinositol 3-kinase-protein kinase B (PKB) /Akt pathway. Pharmacological inhibition of p38 MAPK with SB203580 or expression of a p38 kinase-deficient mutant protein inhibits TGF-β1-induced PKB/Akt phosphorylation. Conditioned medium from TGF-β1-treated cells rapidly induces PKB/Akt activation in an SB203580- and suramin-sensitive manner, suggesting p38 MAPK-dependent production of a secreted growth factor that activates this pro-survival pathway by an autocrine/paracrine mechanism. Inhibition of the phosphatidylinositol 3-kinase-PKB/Akt pathway blocks TGF-β1-induced resistance to apoptosis. These results demonstrate the activation of a novel TGF-β1-activated pro-survival/anti-apoptotic signaling pathway in mesenchymal cells/fibroblasts that may explain cell-specific actions of TGF-β1 and provide mechanistic insights into its pro-fibrotic and tumor-promoting effects. Transforming growth factor-β1 (TGF-β1) 1The abbreviations used are: TGF-β, transforming growth factor-β1; MAP, mitogen-activated protein; MAPK, MAP kinase; PI3K, phosphatidylinositol 3-kinase; EMT, epithelial-mesenchymal transition; DAPI, 4, 6-diamidino-2-phenylindole; PIPES, 1, 4-piperazinediethanesulfonic acid; DMEM, Dulbecco's modified Eagle's medium; FBS, fetal bovine serum; ssDNA, single-stranded DNA; ELISA, enzyme-linked immunosorbent assay; PKB, protein kinase B; ALI, acute lung injury; MC, mesenchymal cells; KM, kinase mutant. is a multifunctional cytokine that regulates a number of biological responses including chemotaxis, cell cycle progression, differentiation, and apoptosis of target cells in a context- and cell-specific manner (1. Massague J. Nat. Rev. Mol. Cell. Biol. 2000; 1: 169-178Crossref PubMed Scopus (1653) Google Scholar, 2. Roberts, A. B. , and Derynck, R. (2001) Science's STKE http: /www. stke. org/cgi/content/full/OCₛigtrans;2001/PE43Google Scholar). TGF-β1 is critically involved in tissue injury and repair processes (3. Border W. A. Ruoslahti E. J. Clin. Investig. 1992; 90: 1-7Crossref PubMed Scopus (1046) Google Scholar, 4. Grande J. P. Proc. Soc. Exp. Biol. Med. 1997; 214: 27-40Crossref PubMed Google Scholar). Rapid release of TGF-β1 at sites of tissue injury is chemotactic for both inflammatory cells (5. Wahl S. M. Hunt D. A. Wakefield L. M. McCartney-Francis N. Wahl L. M. Roberts A. B. Sporn M. B. Proc. Natl. Acad. Sci. U. S. A. 1987; 84: 5788-5792Crossref PubMed Scopus (1101) Google Scholar) and fibroblasts (6. Postlethwaite A. E. Keski-Oja J. Moses H. L. Kang A. H. J. Exp. Med. 1987; 165: 251-256Crossref PubMed Scopus (653) Google Scholar). Pro-angiogenic effects are likely to be important in formation of granulation tissue in the “proliferative” phase of wound healing (7. Roberts A. B. Sporn M. B. Assoian R. K. Smith J. M. Roche N. S. Wakefield L. M. Heine U. I. Liotta L. A. Falanga V. Kehrl J. H. Fauci A. S. Proc. Natl. Acad. Sci. U. S. A. 1986; 83: 4167-4171Crossref PubMed Scopus (2415) Google Scholar). TGF-β1 exerts multiple effects in the later “maturation” phase of wound repair by inducing extracellular matrix production/remodeling (8. Ignotz R. A. Massague J. J. Biol. Chem. 1986; 261: 4337-4345Abstract Full Text PDF PubMed Google Scholar, 9. Tomasek J. J. Gabbiani G. Hinz B. Chaponnier C. Brown R. A. Nat. Rev. Mol. Cell. Biol. 2002; 3: 349-363Crossref PubMed Scopus (3159) Google Scholar) and myofibroblast differentiation (10. Desmouliere A. Geinoz A. Gabbiani F. Gabbiani G. J. Cell Biol. 1993; 122: 103-111Crossref PubMed Scopus (1880) Google Scholar, 11. Thannickal V. J. Lee D. Y. White E. S. Cui Z. Larios J. M. Chacon R. Horowitz J. C. Day R. M. Thomas P. E. J. Biol. Chem. 2003; 278: 12384-12389Abstract Full Text Full Text PDF PubMed Scopus (494) Google Scholar). Apoptosis of fibroblasts/myofibroblasts is essential for the normal resolution of repair responses and the prevention of scarring/fibrosis (12. Desmouliere A. Redard M. Darby I. Gabbiani G. Am. J. Pathol. 1995; 146: 56-66PubMed Google Scholar, 13. Grinnell F. Zhu M. Carlson M. A. Abrams J. M. Exp. Cell Res. 1999; 248: 608-619Crossref PubMed Scopus (239) Google Scholar). The persistence of mesenchymal cells and the up-regulated expression/activation of TGF-β1 at sites of tissue injury and repair are associated with progressive fibrosis with subsequent organ dysfunction in diverse systems including the kidney, liver, and lung (14. Blobe G. C. Schiemann W. P. Lodish H. F. N. Engl. J. Med. 2000; 342: 1350-1358Crossref PubMed Scopus (2189) Google Scholar, 15. Border W. A. Noble N. A. N. Engl. J. Med. 1994; 331: 1286-1292Crossref PubMed Scopus (3014) Google Scholar). The mechanisms by which TGF-β1 regulates apoptosis/survival signals in mesenchymal cells are not well understood. There is better understanding of the growth-inhibitory/pro-apoptotic effects of TGF-β1 on immune cells (16. Brown T. L. Patil S. Cianci C. D. Morrow J. S. Howe P. H. J. Biol. Chem. 1999; 274: 23256-23262Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar) and epithelial cells (17. Dai C. Yang J. Liu Y. J. Biol. Chem. 2003; 278: 12537-12545Abstract Full Text Full Text PDF PubMed Scopus (134) Google Scholar), consistent with its anti-inflammatory and tumor-suppressive functions. In contrast to these “suppressive” functions, TGF-β1 generally promotes growth and survival of mesenchymal cells. Growth-promoting effects of TGF-β1 appear to be primarily mediated by indirect effects on the induction of mitogenic growth factor synthesis (18. Leof E. B. Proper J. A. Goustin A. S. Shipley G. D. DiCorleto P. E. Moses H. L. Proc. Natl. Acad. Sci. U. S. A. 1986; 83: 2453-2457Crossref PubMed Scopus (407) Google Scholar, 19. Finlay G. A. Thannickal V. J. Fanburg B. L. Paulson K. E. J. Biol. Chem. 2000; 275: 27650-27656Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar) and/or their receptor (s) up-regulation (20. Thannickal V. J. Aldweib K. D. Rajan T. Fanburg B. L. Biochem. Biophys. Res. Commun. 1998; 251: 437-441Crossref PubMed Scopus (50) Google Scholar). Relatively few studies have examined direct effects of TGF-β1 on mesenchymal cell/fibroblast apoptosis. Anti-apoptotic effects of TGF-β1 on fibroblasts and myofibroblasts have been reported previously (21. Jelaska A. Korn J. H. Arthritis Rheum. 2000; 43: 2230-2239Crossref PubMed Scopus (144) Google Scholar, 22. Zhang H. Y. Phan S. H. Am. J. Respir. Cell Mol. Biol. 1999; 21: 658-665Crossref PubMed Scopus (301) Google Scholar, 23. Kim G. Jun J. B. Elkon K. B. Arthritis Rheum. 2002; 46: 1504-1511Crossref PubMed Scopus (64) Google Scholar), although mechanisms are not well understood. The phosphatidylinositol 3-kinase (PI3K) -protein kinase B (PKB/Akt) pathway regulates a number of cellular processes including cell cycle progression, glucose metabolism, angiogenesis, cell motility, and apoptosis (24. Brazil D. P. Park J. Hemmings B. A. Cell. 2002; 111: 293-303Abstract Full Text Full Text PDF PubMed Scopus (487) Google Scholar). Multiple targets of PKB/Akt mediate pro-survival/anti-apoptotic effects (reviewed in Ref. 25. Datta S. R. Brunet A. Greenberg M. E. Genes Dev. 1999; 13: 2905-2927Crossref PubMed Scopus (3721) Google Scholar). Activation of the PI3K/Akt pathway in response to TGF-β1 has been demonstrated in epithelial cells where it mediates epithelial-mesenchymal transition (EMT) (26. Bakin A. V. Tomlinson A. K. Bhowmick N. A. Moses H. L. Arteaga C. L. J. Biol. Chem. 2000; 275: 36803-36810Abstract Full Text Full Text PDF PubMed Scopus (830) Google Scholar, 27. Nicolas F. J. Lehmann K. Warne P. H. Hill C. S. Downward J. J. Biol. Chem. 2003; 278: 3251-3256Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar). Moreover, activation of the PKB/Akt pathway has been demonstrated to “rescue” Hep3B cells from TGF-β1-induced apoptosis (28. Chen R. H. Su Y. H. Chuang R. L. Chang T. Y. Oncogene. 1998; 17: 1959-1968Crossref PubMed Scopus (177) Google Scholar). There is limited information, however, on the role and regulation of this pathway by TGF-β1 in mesenchymal cells. TGF-β family members signal via heteromeric transmembrane complexes of type II and type I serine-threonine receptor kinases (1. Massague J. Nat. Rev. Mol. Cell. Biol. 2000; 1: 169-178Crossref PubMed Scopus (1653) Google Scholar, 2. Roberts, A. B. , and Derynck, R. (2001) Science's STKE http: /www. stke. org/cgi/content/full/OCₛigtrans;2001/PE43Google Scholar). The best known direct effectors of TGF-β receptor (s) signaling are the Smad proteins that, when activated, function as transcriptional regulators (1. Massague J. Nat. Rev. Mol. Cell. Biol. 2000; 1: 169-178Crossref PubMed Scopus (1653) Google Scholar). More recently, early post-receptor signaling via Smad-independent pathways have been increasingly recognized (2. Roberts, A. B. , and Derynck, R. (2001) Science's STKE http: /www. stke. org/cgi/content/full/OCₛigtrans;2001/PE43Google Scholar). The p38 mitogen-activated protein kinase (MAPK) appears to be an important transducer of such responses (29. Hanafusa H. Ninomiya-Tsuji J. Masuyama N. Nishita M. Fujisawa J. Shibuya H. Matsumoto K. Nishida E. J. Biol. Chem. 1999; 274: 27161-27167Abstract Full Text Full Text PDF PubMed Scopus (382) Google Scholar, 30. Yu L. Hebert J. 2002; 21: PubMed Scopus Google Scholar, S. S. N. R. M. Mol. Biol. Cell. 2003; PubMed Scopus Google Scholar). direct activation of the p38 MAPK pathway and TGF-β receptor (s) activation appears to be of of apoptosis protein K. S. Ninomiya-Tsuji J. Nishita M. K. K. N. Nishida E. Shibuya H. Matsumoto K. J. 1999; PubMed Scopus Google Scholar, H. K. K. A. Y. N. K. Nishida E. Matsumoto K. PubMed Scopus Google Scholar). Activation of p38 MAPK by TGF-β1 has been to N. A. R. M. M. Moses H. L. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar) or effects in epithelial cells (17. Dai C. Yang J. Liu Y. J. Biol. Chem. 2003; 278: 12537-12545Abstract Full Text Full Text PDF PubMed Scopus (134) Google Scholar, 30. Yu L. Hebert J. 2002; 21: PubMed Scopus Google Scholar, S. S. N. R. M. Mol. Biol. Cell. 2003; PubMed Scopus Google Scholar). The role of the p38 MAPK pathway in the regulation of apoptosis in mesenchymal cells is not well understood. that activation of PI3K/Akt by TGF-β1 may an in mesenchymal cells/fibroblasts and that activation of p38 MAPK may this to effects of TGF-β1 on of of human lung fibroblasts and the role of p38 MAPK-dependent activation in the expression of this human by the at the of mesenchymal cells isolated by from patients with to acute lung injury M. A. N. Engl. J. Med. 2000; 342: PubMed Scopus Google Scholar). in medium of Dulbecco's modified Eagle's medium with fetal bovine serum and medium on of a of cells that for the A. M. M. Clin. Exp. Google Scholar). human fetal lung fibroblasts for and studies at on cell at a of or on cell at a of cells well and in cells for in with to TGF-β1 from and from and from Cell to and p38 MAP kinase from Cell to MAPK from Cell to from to from to and from to single-stranded and against from and from other including from The expression and by of of of cells the the The of to to be for cells. with complexes in I medium for to for The medium by with and for of and as a in cell to Cell in to and as previously V. J. Aldweib K. D. Fanburg B. L. J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). In p38 MAP kinase a from Cell to MAPK to of cell in and at and the and the with and kinase as the The in kinase with and an protein for at The with and the and to followed by with an to for with the of an for to the with A. J. PubMed Scopus Google Scholar). into cell to for and with or TGF-β1 in the of or for to the the for The medium and cells to the with The and the in a for which of to well for at followed by in a the and of bovine serum to well for to The and of to well for of for of to well for followed by by the with an at The of cells and a apoptosis by the by cell by to the cells. by of cells. cells on of tissue to and in medium serum for to for in and with to and subsequent in of in and sites with bovine serum for to the of to for followed by for with for and cells and a and of with for of the on the at TGF-β1 from mesenchymal when isolated from a of cells; may be in cellular and and fetal cells. we examined the effects of TGF-β1 on mesenchymal cells isolated both from patients with acute lung injury and on normal human fetal lung fibroblasts (IMR-90). of apoptosis in the of serum in in cells for in both of cells with TGF-β1 in and cells by and TGF-β1 against apoptosis the of in cells These results that TGF-β1 is to cellular resistance against both and serum deprivation-induced apoptosis in including mesenchymal cells and more of human fetal lung fibroblasts (IMR-90). TGF-β1 Activation of the Smad and p38 MAPK by Activation of the in pathway is known to signals for cell survival (24. Brazil D. P. Park J. Hemmings B. A. Cell. 2002; 111: 293-303Abstract Full Text Full Text PDF PubMed Scopus (487) Google Scholar, 25. Datta S. R. Brunet A. Greenberg M. E. Genes Dev. 1999; 13: 2905-2927Crossref PubMed Scopus (3721) Google Scholar). the pro-survival/anti-apoptotic effects of TGF-β1 on fibroblasts at in be to this we examined the effects of TGF-β1 on PKB/Akt In both and of PKB/Akt as early as TGF-β1 treatment with effects at effects at by treatment with or for to cell not TGF-β1-induced PKB/Akt for and by treatment The delayed responses in PKB/Akt that other more TGF-β1 signals mediate this Rapid signaling from TGF-β receptor (s) activation is best recognized to by the Smad proteins (1. Massague J. Nat. Rev. Mol. Cell. Biol. 2000; 1: 169-178Crossref PubMed Scopus (1653) Google Scholar). studies the of Smad-independent pathways p38 MAPK (2. Roberts, A. B. , and Derynck, R. (2001) Science's STKE http: /www. stke. org/cgi/content/full/OCₛigtrans;2001/PE43Google Scholar, 30. Yu L. Hebert J. 2002; 21: PubMed Scopus Google Scholar). Moreover, p38 MAPK appears to mediate PKB/Akt activation in epithelial cells to M. A. Z. K. Yang C. S. Z. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). p38 MAPK is rapidly in response to TGF-β1 in lung we the of p38 MAPK and it with that of phosphorylation. that both p38 MAPK and are within of TGF-β1 activation of these responses to TGF-β1 is at These results demonstrate that the p38 MAPK pathway is rapidly in response to with to that of and that PKB/Akt be mediated via p38 Pharmacological Inhibition of p38 MAPK TGF-β1-induced PKB/Akt early p38 MAPK activation is for the more delayed activation of we examined the of protein kinase on PKB/Akt phosphorylation. In both and of the MAPK pathway with the on PKB/Akt In the p38 MAPK SB203580 TGF-β1-induced PKB/Akt to in both and cells results when the effects of TGF-β1 examined at and treatment not of kinase more the induction of PKB/Akt by in and in cells In the of the PKB/Akt in cells and PKB/Akt to of in and the kinase PKB/Akt to a in in cells. these results that inhibition of the p38 MAPK pathway and blocks TGF-β1-induced PKB/Akt more and cell-specific responses are with an of kinase may at H. M. Biochem. J. 2000; PubMed Scopus Google Scholar). SB203580 may although the are for p38 MAPK H. M. Biochem. J. 2000; PubMed Scopus Google Scholar). In that at a of SB203580 inhibits p38 MAPK PKB/Akt is by H. M. Biochem. J. 2000; PubMed Scopus Google Scholar). better at which SB203580 inhibits TGF-β1-induced PKB/Akt we a by cells with and of SB203580 and TGF-β1 for inhibition of TGF-β1-induced PKB/Akt phosphorylation. inhibition at and inhibition at at inhibition of the of PKB/Akt Moreover, SB203580 the of on PKB/Akt in these cells not These that the of TGF-β1 PKB/Akt is more likely to effects of SB203580 on p38 MAPK activation to more direct effects of this on PKB/Akt by TGF-β1 on p38 MAPK the role of p38 MAPK activation in TGF-β1-induced PKB/Akt we cell of cells a p38 MAPK a and TGF-β1 for of p38 MAPK in cell p38 MAPK by in of not in cells at the consistent with p38 MAPK in these cells. of not appear to the in response to and to be cells. The of with PKB/Akt by TGF-β1 in cell TGF-β1-induced PKB/Akt in cells and Moreover, the activation of this pathway appears to be important for TGF-β1-induced cell a of myofibroblast differentiation, this response is in cells These results that activation of p38 MAPK by TGF-β1 is for the induction of PKB/Akt and that activation of this pathway may be more for pro-survival signaling for myofibroblast effects of The of these cell in the and of TGF-β1 of serum examined cells demonstrated with of cells more in These the that activation of the p38 MAPK pathway is important for the pro-survival effects of TGF-β1 in TGF-β1-induced PKB/Akt Activation by p38 MAPK delayed of PKB/Akt to the early and rapid activation of p38 MAPK in response to TGF-β1 that production of an factor may this pro-survival pathway in an this we examined the effects of medium from and TGF-β1-treated cells on the activation of PKB/Akt in cells. PKB/Akt is rapidly within when medium from cells with TGF-β1 for is to cells; is with medium from cells and that the secreted for activation of PKB/Akt may be at in cells and that this production may be up-regulated by this by at the cell cells with a of growth factor receptor activation that by the of growth factor to their extracellular C. A. R. A. Cell. 1994; Full Text PDF PubMed Scopus Google Scholar). the activation of PKB/Akt by medium from both and TGF-β1-treated cells and suggesting the of a secreted that mediates this via a mechanism. the production of this factor on the early activation of p38 MAPK by medium from cells with TGF-β1 in the of SB203580 to and early responses on PKB/Akt TGF-β1 PKB/Akt when this medium in the of the p38 MAPK not by the these results that activation of p38 MAPK is for the of a growth that mediates rapid activation of the pathway in an autocrine/paracrine to Apoptosis to in by pathway has been to pro-survival/anti-apoptotic signaling S. R. Brunet A. Greenberg M. E. Genes Dev. 1999; 13: 2905-2927Crossref PubMed Scopus (3721) Google Scholar). activation of this pathway is essential for effects of we examined the of the on apoptosis. Inhibition of the of TGF-β1 on serum deprivation-induced apoptosis is when apoptosis is by the number of cells that for B and These results that activation of the pathway is for induction of the in mesenchymal cells/fibroblasts to TGF-β1 is a multifunctional cytokine that mediates and responses in of tissue injury as well as in other processes such as TGF-β1 actions are of epithelial cells is that of fibroblasts is These are of the repair in progressive The results of this that the pro-survival/anti-apoptotic of human lung cells by TGF-β1 is at in by activation of the pathway. demonstrate that activation of is mediated by a secreted growth production is on early activation of p38 MAPK by TGF-β receptor (s) epithelial and mesenchymal cells in the response to TGF-β1 have been the mechanisms are (1. Massague J. Nat. Rev. Mol. Cell. Biol. 2000; 1: 169-178Crossref PubMed Scopus (1653) Google Scholar). The results of that in the activation and of post-receptor signaling pathways may in for the in cell-specific There is better understanding of TGF-β1 signaling by Smad-independent pathways in epithelial cells in mesenchymal cells. There is that TGF-β1-induced p38 MAPK activation in epithelial cells to responses (17. Dai C. Yang J. Liu Y. J. Biol. Chem. 2003; 278: 12537-12545Abstract Full Text Full Text PDF PubMed Scopus (134) Google Scholar, 30. Yu L. Hebert J. 2002; 21: PubMed Scopus Google Scholar, S. S. N. R. M. Mol. Biol. Cell. 2003; PubMed Scopus Google Scholar), a consistent with of E. S. Thannickal V. J. J. Pathol. 2003; PubMed Scopus Google Scholar). when the pathway is in epithelial cells by a biological that of EMT, may (26. Bakin A. V. Tomlinson A. K. Bhowmick N. A. Moses H. L. Arteaga C. L. J. Biol. Chem. 2000; 275: 36803-36810Abstract Full Text Full Text PDF PubMed Scopus (830) Google Scholar). 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