Stress activated protein kinase p38 is involved in IL-6 induced transcriptional activation of STAT3

The pleiotropic cytokine interleukin-6 (IL-6) induces acute phase protein expression in HepG2 human hepatoma cells and promotes the growth of mouse B9 hybridoma. The signaling cascades leading to these biological functions are only partially known. We analysed the involvement of MAPK homologues in IL-6 transduction pathways and found that interleukin-6 triggered activation of p38 stress-activated protein kinase (p38) but not of jun kinase. p38 activity was required for biological functions including acute phase protein secretion from HepG2 hepatoma and proliferation of B9 hybridoma cells. Using a reporter gene construct containing a 190 bp promoter fragment of the acute phase protein haptoglobin we found that p38 is involved in transcriptional activation of the haptoglobin promoter by STAT3 but not by NF-IL6. Thus, we present evidence for a role of p38 in IL-6 induced functions and a possible cross-talk between this MAPK homologue and the STAT pathway.

[1]  S. Akira,et al.  Molecular cloning of APRF, a novel IFN-stimulated gene factor 3 p91-related transcription factor involved in the gp130-mediated signaling pathway , 1994, Cell.

[2]  S. Akira,et al.  Phosphorylation at threonine-235 by a ras-dependent mitogen-activated protein kinase cascade is essential for transcription factor NF-IL6. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[3]  Philip R. Cohen,et al.  PD 098059 Is a Specific Inhibitor of the Activation of Mitogen-activated Protein Kinase Kinase in Vitro and in Vivo(*) , 1995, The Journal of Biological Chemistry.

[4]  J. Darnell,et al.  Choice of STATs and other substrates specified by modular tyrosine-based motifs in cytokine receptors , 1995, Science.

[5]  L. Rawlinson,et al.  T Cell Proliferation in Response to Interleukins 2 and 7 Requires p38MAP Kinase Activation* , 1997, The Journal of Biological Chemistry.

[6]  J. Gauldie,et al.  IL6 and the acute phase reaction. , 1992, Research in immunology.

[7]  J. Darnell,et al.  A common nuclear signal transduction pathway activated by growth factor and cytokine receptors. , 1993, Science.

[8]  H. Nishina,et al.  Activation of Stress-activated Protein Kinases/c-Jun N-terminal Protein Kinases (SAPKs/JNKs) by a Novel Mitogen-activated Protein Kinase Kinase (MKK7)* , 1997, The Journal of Biological Chemistry.

[9]  Michel Morange,et al.  A novel kinase cascade triggered by stress and heat shock that stimulates MAPKAP kinase-2 and phosphorylation of the small heat shock proteins , 1994, Cell.

[10]  J. Darnell,et al.  Maximal activation of transcription by statl and stat3 requires both tyrosine and serine phosphorylation , 1995, Cell.

[11]  Xiaozhong Wang,et al.  Stress-Induced Phosphorylation and Activation of the Transcription Factor CHOP (GADD153) by p38 MAP Kinase , 1996, Science.

[12]  L. Tong,et al.  A highly specific inhibitor of human p38 MAP kinase binds in the ATP pocket , 1997, Nature Structural Biology.

[13]  T. Hirano,et al.  Interleukin-6 triggers the association of its receptor with a possible signal transducer, gp130 , 1989, Cell.

[14]  P. Heinrich,et al.  Acute-phase response factor, a nuclear factor binding to acute-phase response elements, is rapidly activated by interleukin-6 at the posttranslational level , 1993, Molecular and cellular biology.

[15]  C. Marshall,et al.  Specificity of receptor tyrosine kinase signaling: Transient versus sustained extracellular signal-regulated kinase activation , 1995, Cell.

[16]  V. De Filippis,et al.  Structure, stability and biological properties of a N-terminally truncated form of recombinant human interleukin-6 containing a single disulfide bond. , 1995, European journal of biochemistry.

[17]  J. Ihle,et al.  STATs and MAPKs: obligate or opportunistic partners in signaling. , 1996, BioEssays : news and reviews in molecular, cellular and developmental biology.

[18]  L. Aarden,et al.  Functional discrimination between interleukin 6 and interleukin 1 , 1988, European journal of immunology.

[19]  R. Cortese,et al.  The human haptoglobin gene promoter: interleukin‐6‐responsive elements interact with a DNA‐binding protein induced by interleukin‐6. , 1989, The EMBO journal.

[20]  T. Hirano,et al.  Interleukin-6-induced tyrosine phosphorylation of multiple proteins in murine hematopoietic lineage cells. , 1994, Biochemical and biophysical research communications.

[21]  K. Yasukawa,et al.  IL-6-induced homodimerization of gp130 and associated activation of a tyrosine kinase. , 1993, Science.

[22]  E. Petricoin,et al.  Requirement for MAP kinase (ERK2) activity in interferon alpha- and interferon beta-stimulated gene expression through STAT proteins. , 1995, Science.

[23]  E. Nishida,et al.  Activation of p38 MAP kinase pathway by erythropoietin and interleukin-3. , 1997, Blood.

[24]  R. Plevin,et al.  Stress-activated protein kinases: activation, regulation and function. , 1997, Cellular signalling.

[25]  Philip R. Cohen,et al.  Identification of novel phosphorylation sites required for activation of MAPKAP kinase‐2. , 1995, The EMBO journal.

[26]  S. Leevers,et al.  Activation of extracellular signal‐regulated kinase, ERK2, by p21ras oncoprotein. , 1992, The EMBO journal.

[27]  D. Zechner,et al.  A Role for the p38 Mitogen-activated Protein Kinase Pathway in Myocardial Cell Growth, Sarcomeric Organization, and Cardiac-specific Gene Expression , 1997, The Journal of cell biology.

[28]  G. G. Stokes.  "J." , 1890, The New Yale Book of Quotations.

[29]  J. Blenis,et al.  Requirement of serine phosphorylation for formation of STAT-promoter complexes. , 1995, Science.

[30]  H. Baumann,et al.  Distinct regulation of the interleukin-1 and interleukin-6 response elements of the rat haptoglobin gene in rat and human hepatoma cells , 1990, Molecular and cellular biology.

[31]  P. Cohen,et al.  The search for physiological substrates of MAP and SAP kinases in mammalian cells. , 1997, Trends in cell biology.

[32]  C. Schindler,et al.  Association of transcription factor APRF and protein kinase Jak1 with the interleukin-6 signal transducer gp130. , 1994, Science.

[33]  J. Hsuan,et al.  Interleukin-1 activates a novel protein kinase cascade that results in the phosphorylation of hsp27 , 1994, Cell.

[34]  L. Zon,et al.  Role of SAPK/ERK kinase-1 in the stress-activated pathway regulating transcription factor c-Jun , 1994, Nature.

[35]  M. Karin,et al.  Identification of a dual specificity kinase that activates the Jun kinases and p38-Mpk2. , 1995, Science.

[36]  W. Fiers,et al.  The p38/RK mitogen‐activated protein kinase pathway regulates interleukin‐6 synthesis response to tumor necrosis factor. , 1996, The EMBO journal.

[37]  Jiahuai Han,et al.  Independent human MAP-kinase signal transduction pathways defined by MEK and MKK isoforms , 1995, Science.

[38]  P. Cohen,et al.  MAPKAP kinase‐2; a novel protein kinase activated by mitogen‐activated protein kinase. , 1992, The EMBO journal.

[39]  Jerry L. Adams,et al.  A protein kinase involved in the regulation of inflammatory cytokine biosynthesis , 1994, Nature.

[40]  T. Kishimoto,et al.  gp130, common signal transducer for cytokines including IL-6 , 1993 .

[41]  E. Nishida,et al.  A novel SAPK/JNK kinase, MKK7, stimulated by TNFα and cellular stresses , 1997, The EMBO journal.

[42]  John C. Lee,et al.  Hemopoietic Growth Factors with the Exception of Interleukin-4 Activate the p38 Mitogen-activated Protein Kinase Pathway* , 1997, The Journal of Biological Chemistry.

[43]  H. Baumann,et al.  STAT3 and STAT5B Are Targets of Two Different Signal Pathways Activated by Hematopoietin Receptors and Control Transcription via Separate Cytokine Response Elements (*) , 1995, The Journal of Biological Chemistry.

[44]  G. Ciliberto,et al.  Two distinct and independent sites on IL‐6 trigger gp 130 dimer formation and signalling. , 1995, The EMBO journal.

[45]  J. Gauldie,et al.  The acute phase response. , 1994, Immunology today.

[46]  Jiahuai Han,et al.  The Stress Inducer Arsenite Activates Mitogen-activated Protein Kinases Extracellular Signal-regulated Kinases 1 and 2 via a MAPK Kinase 6/p38-dependent Pathway* , 1998, The Journal of Biological Chemistry.

[47]  T. Hirano,et al.  Molecular cloning and expression of an IL-6 signal transducer, gp130 , 1990, Cell.

[48]  Philip R. Cohen,et al.  SB 203580 is a specific inhibitor of a MAP kinase homologue which is stimulated by cellular stresses and interleukin‐1 , 1995, FEBS letters.

[49]  Steven A. Carr,et al.  Pyridinyl Imidazole Inhibitors of p38 Mitogen-activated Protein Kinase Bind in the ATP Site* , 1997, The Journal of Biological Chemistry.

[50]  T. Kishimoto,et al.  The biology of interleukin-6. , 1989, Blood.

[51]  R. Davis,et al.  MKK3- and MKK6-regulated gene expression is mediated by the p38 mitogen-activated protein kinase signal transduction pathway , 1996, Molecular and cellular biology.

[52]  H. Kim,et al.  The Carboxyl-terminal Region of STAT3 Controls Gene Induction by the Mouse Haptoglobin Promoter* , 1997, The Journal of Biological Chemistry.