• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of embojLink to Publisher's site
EMBO J. Jul 1, 1998; 17(13): 3660–3668.
PMCID: PMC1170702

Stat1 combines signals derived from IFN-gamma and LPS receptors during macrophage activation.

Abstract

Complete activation of macrophages during immune responses results from stimulation with the activating cytokine interferon-gamma (IFN-gamma) and a second stimulus, usually a microbial product. Bacterial infection of macrophages, or treatment with bacterial lipopolysaccharide (LPS), resulted in rapid Stat1 phosphorylation on Ser727 (S727) independently of concomitant tyrosine phosphorylation. IFN-gamma also caused rapid phosphorylation of S727. In both situations, S727 phosphorylation was reduced by pre-treatment of cells with the serine kinase inhibitor H7. When macrophages were treated sequentially or simultaneously with LPS and IFN-gamma, the pool of molecules phosphorylated on both Tyr701 (Y701) and S727 was strongly increased. Consistently, Stat1-dependent transcription in response to IFN-gamma was significantly enhanced if the cells were pre-treated with bacterial LPS. The relative amount of S727-phosphorylated Stat1 in the non-tyrosine phosphorylated fraction was considerably smaller than that in the tyrosine-phosphorylated fraction. No evidence was found for an effect of S727 phosphorylation on the phosphorylation of Y701 by IFN-gamma. Thus, serine and tyrosine phosphorylation of Stat1 are caused independently of each other, but the serine kinase may recognize tyrosine-phosphorylated Stat1 preferentially in the course of an IFN-gamma response. The data suggest Stat1 to be a convergence point for immunological stimuli in a macrophage proinflammatory response.

Full Text

The Full Text of this article is available as a PDF (411K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Baccarini M, Bistoni F, Lohmann-Matthes ML. In vitro natural cell-mediated cytotoxicity against Candida albicans: macrophage precursors as effector cells. J Immunol. 1985 Apr;134(4):2658–2665. [PubMed]
  • Baeuerle PA, Baltimore D. NF-kappa B: ten years after. Cell. 1996 Oct 4;87(1):13–20. [PubMed]
  • Baeuerle PA, Henkel T. Function and activation of NF-kappa B in the immune system. Annu Rev Immunol. 1994;12:141–179. [PubMed]
  • Beadling C, Ng J, Babbage JW, Cantrell DA. Interleukin-2 activation of STAT5 requires the convergent action of tyrosine kinases and a serine/threonine kinase pathway distinct from the Raf1/ERK2 MAP kinase pathway. EMBO J. 1996 Apr 15;15(8):1902–1913. [PMC free article] [PubMed]
  • Boulton TG, Zhong Z, Wen Z, Darnell JE, Jr, Stahl N, Yancopoulos GD. STAT3 activation by cytokines utilizing gp130 and related transducers involves a secondary modification requiring an H7-sensitive kinase. Proc Natl Acad Sci U S A. 1995 Jul 18;92(15):6915–6919. [PMC free article] [PubMed]
  • Büscher D, Hipskind RA, Krautwald S, Reimann T, Baccarini M. Ras-dependent and -independent pathways target the mitogen-activated protein kinase network in macrophages. Mol Cell Biol. 1995 Jan;15(1):466–475. [PMC free article] [PubMed]
  • Caldenhoven E, Coffer P, Yuan J, Van de Stolpe A, Horn F, Kruijer W, Van der Saag PT. Stimulation of the human intercellular adhesion molecule-1 promoter by interleukin-6 and interferon-gamma involves binding of distinct factors to a palindromic response element. J Biol Chem. 1994 Aug 19;269(33):21146–21154. [PubMed]
  • Cho SS, Bacon CM, Sudarshan C, Rees RC, Finbloom D, Pine R, O'Shea JJ. Activation of STAT4 by IL-12 and IFN-alpha: evidence for the involvement of ligand-induced tyrosine and serine phosphorylation. J Immunol. 1996 Dec 1;157(11):4781–4789. [PubMed]
  • Chung J, Uchida E, Grammer TC, Blenis J. STAT3 serine phosphorylation by ERK-dependent and -independent pathways negatively modulates its tyrosine phosphorylation. Mol Cell Biol. 1997 Nov;17(11):6508–6516. [PMC free article] [PubMed]
  • Darnell JE., Jr STATs and gene regulation. Science. 1997 Sep 12;277(5332):1630–1635. [PubMed]
  • Darnell JE, Jr, Kerr IM, Stark GR. Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science. 1994 Jun 3;264(5164):1415–1421. [PubMed]
  • David M, Petricoin E, 3rd, Benjamin C, Pine R, Weber MJ, Larner AC. Requirement for MAP kinase (ERK2) activity in interferon alpha- and interferon beta-stimulated gene expression through STAT proteins. Science. 1995 Sep 22;269(5231):1721–1723. [PubMed]
  • Decker T, Kovarik P, Meinke A. GAS elements: a few nucleotides with a major impact on cytokine-induced gene expression. J Interferon Cytokine Res. 1997 Mar;17(3):121–134. [PubMed]
  • Deng W, Ohmori Y, Hamilton TA. LPS does not directly induce STAT activity in mouse macrophages. Cell Immunol. 1996 May 25;170(1):20–24. [PubMed]
  • Durbin JE, Hackenmiller R, Simon MC, Levy DE. Targeted disruption of the mouse Stat1 gene results in compromised innate immunity to viral disease. Cell. 1996 Feb 9;84(3):443–450. [PubMed]
  • Eilers A, Baccarini M, Horn F, Hipskind RA, Schindler C, Decker T. A factor induced by differentiation signals in cells of the macrophage lineage binds to the gamma interferon activation site. Mol Cell Biol. 1994 Feb;14(2):1364–1373. [PMC free article] [PubMed]
  • Eilers A, Georgellis D, Klose B, Schindler C, Ziemiecki A, Harpur AG, Wilks AF, Decker T. Differentiation-regulated serine phosphorylation of STAT1 promotes GAF activation in macrophages. Mol Cell Biol. 1995 Jul;15(7):3579–3586. [PMC free article] [PubMed]
  • Gao J, Morrison DC, Parmely TJ, Russell SW, Murphy WJ. An interferon-gamma-activated site (GAS) is necessary for full expression of the mouse iNOS gene in response to interferon-gamma and lipopolysaccharide. J Biol Chem. 1997 Jan 10;272(2):1226–1230. [PubMed]
  • Gouilleux F, Pallard C, Dusanter-Fourt I, Wakao H, Haldosen LA, Norstedt G, Levy D, Groner B. Prolactin, growth hormone, erythropoietin and granulocyte-macrophage colony stimulating factor induce MGF-Stat5 DNA binding activity. EMBO J. 1995 May 1;14(9):2005–2013. [PMC free article] [PubMed]
  • Hambleton J, Weinstein SL, Lem L, DeFranco AL. Activation of c-Jun N-terminal kinase in bacterial lipopolysaccharide-stimulated macrophages. Proc Natl Acad Sci U S A. 1996 Apr 2;93(7):2774–2778. [PMC free article] [PubMed]
  • Joseph CK, Wright SD, Bornmann WG, Randolph JT, Kumar ER, Bittman R, Liu J, Kolesnick RN. Bacterial lipopolysaccharide has structural similarity to ceramide and stimulates ceramide-activated protein kinase in myeloid cells. J Biol Chem. 1994 Jul 1;269(26):17606–17610. [PubMed]
  • Kielian TL, Blecha F. CD14 and other recognition molecules for lipopolysaccharide: a review. Immunopharmacology. 1995 Apr;29(3):187–205. [PubMed]
  • Kirken RA, Malabarba MG, Xu J, DaSilva L, Erwin RA, Liu X, Hennighausen L, Rui H, Farrar WL. Two discrete regions of interleukin-2 (IL2) receptor beta independently mediate IL2 activation of a PD98059/rapamycin/wortmannin-insensitive Stat5a/b serine kinase. J Biol Chem. 1997 Jun 13;272(24):15459–15465. [PubMed]
  • Kirken RA, Malabarba MG, Xu J, Liu X, Farrar WL, Hennighausen L, Larner AC, Grimley PM, Rui H. Prolactin stimulates serine/tyrosine phosphorylation and formation of heterocomplexes of multiple Stat5 isoforms in Nb2 lymphocytes. J Biol Chem. 1997 May 30;272(22):14098–14103. [PubMed]
  • Leaman DW, Leung S, Li X, Stark GR. Regulation of STAT-dependent pathways by growth factors and cytokines. FASEB J. 1996 Dec;10(14):1578–1588. [PubMed]
  • Ledebur HC, Parks TP. Transcriptional regulation of the intercellular adhesion molecule-1 gene by inflammatory cytokines in human endothelial cells. Essential roles of a variant NF-kappa B site and p65 homodimers. J Biol Chem. 1995 Jan 13;270(2):933–943. [PubMed]
  • Look DC, Pelletier MR, Holtzman MJ. Selective interaction of a subset of interferon-gamma response element-binding proteins with the intercellular adhesion molecule-1 (ICAM-1) gene promoter controls the pattern of expression on epithelial cells. J Biol Chem. 1994 Mar 25;269(12):8952–8958. [PubMed]
  • Lütticken C, Coffer P, Yuan J, Schwartz C, Caldenhoven E, Schindler C, Kruijer W, Heinrich PC, Horn F. Interleukin-6-induced serine phosphorylation of transcription factor APRF: evidence for a role in interleukin-6 target gene induction. FEBS Lett. 1995 Feb 27;360(2):137–143. [PubMed]
  • Meng F, Lowell CA. Lipopolysaccharide (LPS)-induced macrophage activation and signal transduction in the absence of Src-family kinases Hck, Fgr, and Lyn. J Exp Med. 1997 May 5;185(9):1661–1670. [PMC free article] [PubMed]
  • Meraz MA, White JM, Sheehan KC, Bach EA, Rodig SJ, Dighe AS, Kaplan DH, Riley JK, Greenlund AC, Campbell D, et al. Targeted disruption of the Stat1 gene in mice reveals unexpected physiologic specificity in the JAK-STAT signaling pathway. Cell. 1996 Feb 9;84(3):431–442. [PubMed]
  • Morgan C, Pollard JW, Stanley ER. Isolation and characterization of a cloned growth factor dependent macrophage cell line, BAC1.2F5. J Cell Physiol. 1987 Mar;130(3):420–427. [PubMed]
  • Müller M, Ibelgaufts H, Kerr IM. Interferon response pathways--a paradigm for cytokine signalling? J Viral Hepat. 1994;1(2):87–103. [PubMed]
  • Nacy CA, Meltzer MS. T-cell-mediated activation of macrophages. Curr Opin Immunol. 1991 Jun;3(3):330–335. [PubMed]
  • Ng J, Cantrell D. STAT3 is a serine kinase target in T lymphocytes. Interleukin 2 and T cell antigen receptor signals converge upon serine 727. J Biol Chem. 1997 Sep 26;272(39):24542–24549. [PubMed]
  • Nishiya T, Uehara T, Edamatsu H, Kaziro Y, Itoh H, Nomura Y. Activation of Stat1 and subsequent transcription of inducible nitric oxide synthase gene in C6 glioma cells is independent of interferon-gamma-induced MAPK activation that is mediated by p21ras. FEBS Lett. 1997 May 12;408(1):33–38. [PubMed]
  • Pine R. Convergence of TNFalpha and IFNgamma signalling pathways through synergistic induction of IRF-1/ISGF-2 is mediated by a composite GAS/kappaB promoter element. Nucleic Acids Res. 1997 Nov 1;25(21):4346–4354. [PMC free article] [PubMed]
  • Reimann T, Büscher D, Hipskind RA, Krautwald S, Lohmann-Matthes ML, Baccarini M. Lipopolysaccharide induces activation of the Raf-1/MAP kinase pathway. A putative role for Raf-1 in the induction of the IL-1 beta and the TNF-alpha genes. J Immunol. 1994 Dec 15;153(12):5740–5749. [PubMed]
  • Sanghera JS, Weinstein SL, Aluwalia M, Girn J, Pelech SL. Activation of multiple proline-directed kinases by bacterial lipopolysaccharide in murine macrophages. J Immunol. 1996 Jun 1;156(11):4457–4465. [PubMed]
  • Schindler C. Cytokine signal transduction. Receptor. 1995 Spring;5(1):51–62. [PubMed]
  • Sims SH, Cha Y, Romine MF, Gao PQ, Gottlieb K, Deisseroth AB. A novel interferon-inducible domain: structural and functional analysis of the human interferon regulatory factor 1 gene promoter. Mol Cell Biol. 1993 Jan;13(1):690–702. [PMC free article] [PubMed]
  • Strehlow I, Seegert D, Frick C, Bange FC, Schindler C, Böttger EC, Decker T. The gene encoding IFP 53/tryptophanyl-tRNA synthetase is regulated by the gamma-interferon activation factor. J Biol Chem. 1993 Aug 5;268(22):16590–16595. [PubMed]
  • Sweet MJ, Hume DA. Endotoxin signal transduction in macrophages. J Leukoc Biol. 1996 Jul;60(1):8–26. [PubMed]
  • Tsukada J, Waterman WR, Koyama Y, Webb AC, Auron PE. A novel STAT-like factor mediates lipopolysaccharide, interleukin 1 (IL-1), and IL-6 signaling and recognizes a gamma interferon activation site-like element in the IL1B gene. Mol Cell Biol. 1996 May;16(5):2183–2194. [PMC free article] [PubMed]
  • Viriyakosol S, Kirkland TN. A region of human CD14 required for lipopolysaccharide binding. J Biol Chem. 1995 Jan 6;270(1):361–368. [PubMed]
  • Wen Z, Darnell JE., Jr Mapping of Stat3 serine phosphorylation to a single residue (727) and evidence that serine phosphorylation has no influence on DNA binding of Stat1 and Stat3. Nucleic Acids Res. 1997 Jun 1;25(11):2062–2067. [PMC free article] [PubMed]
  • Wen Z, Zhong Z, Darnell JE., Jr Maximal activation of transcription by Stat1 and Stat3 requires both tyrosine and serine phosphorylation. Cell. 1995 Jul 28;82(2):241–250. [PubMed]
  • Woldman I, Mellitzer G, Kieslinger M, Buchhart D, Meinke A, Beug H, Decker T. STAT5 involvement in the differentiation response of primary chicken myeloid progenitor cells to chicken myelomonocytic growth factor. J Immunol. 1997 Jul 15;159(2):877–886. [PubMed]
  • Wright SD, Kolesnick RN. Does endotoxin stimulate cells by mimicking ceramide? Immunol Today. 1995 Jun;16(6):297–302. [PubMed]
  • Xie QW, Kashiwabara Y, Nathan C. Role of transcription factor NF-kappa B/Rel in induction of nitric oxide synthase. J Biol Chem. 1994 Feb 18;269(7):4705–4708. [PubMed]
  • Zhang JJ, Vinkemeier U, Gu W, Chakravarti D, Horvath CM, Darnell JE., Jr Two contact regions between Stat1 and CBP/p300 in interferon gamma signaling. Proc Natl Acad Sci U S A. 1996 Dec 24;93(26):15092–15096. [PMC free article] [PubMed]
  • Zhang X, Blenis J, Li HC, Schindler C, Chen-Kiang S. Requirement of serine phosphorylation for formation of STAT-promoter complexes. Science. 1995 Mar 31;267(5206):1990–1994. [PubMed]
  • Zhu X, Wen Z, Xu LZ, Darnell JE., Jr Stat1 serine phosphorylation occurs independently of tyrosine phosphorylation and requires an activated Jak2 kinase. Mol Cell Biol. 1997 Nov;17(11):6618–6623. [PMC free article] [PubMed]

Articles from The EMBO Journal are provided here courtesy of The European Molecular Biology Organization

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

  • Compound
    Compound
    PubChem Compound links
  • MedGen
    MedGen
    Related information in MedGen
  • PubMed
    PubMed
    PubMed citations for these articles
  • Substance
    Substance
    PubChem Substance links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...