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Journal of Neuroinflammation

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Open Access 01-12-2012 | Research

LPS-induced release of IL-6 from glia modulates production of IL-1β in a JAK2-dependent manner

Authors: Aedín M Minogue, James P Barrett, Marina A Lynch

Published in: Journal of Neuroinflammation | Issue 1/2012

Abstract

Background

Compelling evidence has implicated neuroinflammation in the pathogenesis of a number of neurodegenerative conditions. Chronic activation of both astrocytes and microglia leads to excessive secretion of proinflammatory molecules such as TNFα, IL-6 and IL-1β with potentially deleterious consequences for neuronal viability. Many signaling pathways involving the mitogen-activated protein kinases (MAPKs), nuclear factor κB (NFκB) complex and the Janus kinases (JAKs)/signal transducers and activators of transcription (STAT)-1 have been implicated in the secretion of proinflammatory cytokines from glia. We sought to identify signaling kinases responsible for cytokine production and to delineate the complex interactions which govern time-related responses to lipopolysaccharide (LPS).

Methods

We examined the time-related changes in certain signaling events and the release of proinflammatory cytokines from LPS-stimulated co-cultures of astrocytes and microglia isolated from neonatal rats.

Results

TNFα was detected in the supernatant approximately 1 to 2 hours after LPS treatment while IL-1β and IL-6 were detected after 2 to 3 and 4 to 6 hours, respectively. Interestingly, activation of NFκB signaling preceded release of all cytokines while phosphorylation of STAT1 was evident only after 2 hours, indicating that activation of JAK/STAT may be important in the up-regulation of IL-6 production. Additionally, incubation of glia with TNFα induced both phosphorylation of JAK2 and STAT1 and the interaction of JAK2 with the TNFα receptor (TNFR1). Co-treatment of glia with LPS and recombinant IL-6 protein attenuated the LPS-induced release of both TNFα and IL-1β while potentiating the effect of LPS on suppressor of cytokine signaling (SOCS)3 expression and IL-10 release.

Conclusions

These data indicate that TNFα may regulate IL-6 production through activation of JAK/STAT signaling and that the subsequent production of IL-6 may impact on the release of TNFα, IL-1β and IL-10.

Benarroch EE: Neuron-astrocyte interactions: partnership for normal function and disease in the central nervous system. Mayo Clin Proc 2005, 80:1326–1338.CrossRefPubMed

Cacabelos R, Alvarez XA, Franco-Maside A, Fernandez-Novoa L, Caamano J: Serum tumor necrosis factor (TNF) in Alzheimer’s disease and multi-infarct dementia. Methods Find Exp Clin Pharmacol 1994, 16:29–35.PubMed

McGeer PL, Itagaki S, Boyes BE, McGeer EG: Reactive microglia are positive for HLA-DR in the substantia nigra of Parkinson’s and Alzheimer’s disease brains. Neurology 1988, 38:1285–1291.CrossRefPubMed

Griffin WS, Stanley LC, Ling C, White L, MacLeod V, Perrot LJ, White CL, Araoz C: Brain interleukin 1 and S-100 immunoreactivity are elevated in Down syndrome and Alzheimer disease. Proc Natl Acad Sci U S A 1989, 86:7611–7615.CrossRefPubMedPubMedCentral

Wood JA, Wood PL, Ryan R, Graff-Radford NR, Pilapil C, Robitaille Y, Quirion R: Cytokine indices in Alzheimer’s temporal cortex: no changes in mature IL-1 beta or IL-1RA but increases in the associated acute phase proteins IL-6, alpha 2-macroglobulin and C-reactive protein. Brain Res 1993, 629:245–252.CrossRefPubMed

Galanos C, Freudenberg MA: Mechanisms of endotoxin shock and endotoxin hypersensitivity. Immunobiology 1993, 187:346–356.CrossRefPubMed

Olson JK, Miller SD: Microglia initiate central nervous system innate and adaptive immune responses through multiple TLRs. J Immunol 2004, 173:3916–3924.CrossRefPubMed

Qin H, Wilson CA, Lee SJ, Zhao X, Benveniste EN: LPS induces CD40 gene expression through the activation of NF-kappaB and STAT-1alpha in macrophages and microglia. Blood 2005, 106:3114–3122.CrossRefPubMedPubMedCentral

Kurzer JH, Argetsinger LS, Zhou YJ, Kouadio JL, O’Shea JJ, Carter-Su C: Tyrosine 813 is a site of JAK2 autophosphorylation critical for activation of JAK2 by SH2-B beta. Mol Cell Biol 2004, 24:4557–4570.CrossRefPubMedPubMedCentral

10.

Oh JW, Van Wagoner NJ, Rose-John S, Benveniste EN: Role of IL-6 and the soluble IL-6 receptor in inhibition of VCAM-1 gene expression. J Immunol 1998, 161:4992–4999.PubMed

11.

Nolan Y, Martin D, Campbell VA, Lynch MA: Evidence of a protective effect of phosphatidylserine-containing liposomes on lipopolysaccharide-induced impairment of long-term potentiation in the rat hippocampus. J Neuroimmunol 2004, 151:12–23.CrossRefPubMed

12.

Lyons A, Downer EJ, Crotty S, Nolan YM, Mills KH, Lynch MA: CD200 ligand receptor interaction modulates microglial activation in vivo and in vitro: a role for IL-4. J Neurosci 2007, 27:8309–8313.CrossRefPubMed

13.

Bacon CM, McVicar DW, Ortaldo JR, Rees RC, O’Shea JJ, Johnston JA: Interleukin 12 (IL-12) induces tyrosine phosphorylation of JAK2 and TYK2: differential use of Janus family tyrosine kinases by IL-2 and IL-12. J Exp Med 1995, 181:399–404.CrossRefPubMed

14.

Parganas E, Wang D, Stravopodis D, Topham DJ, Marine JC, Teglund S, Vanin EF, Bodner S, Colamonici OR, van Deursen JM, Grosveld G, Ihle JN: Jak2 is essential for signaling through a variety of cytokine receptors. Cell 1998, 93:385–395.CrossRefPubMed

15.

Jones SA: Directing transition from innate to acquired immunity: defining a role for IL-6. J Immunol 2005, 175:3463–3468.CrossRefPubMed

16.

Samoilova EB, Horton JL, Hilliard B, Liu TS, Chen Y: IL-6-deficient mice are resistant to experimental autoimmune encephalomyelitis: roles of IL-6 in the activation and differentiation of autoreactive T cells. J Immunol 1998, 161:6480–6486.PubMed

17.

Kopf M, Baumann H, Freer G, Freudenberg M, Lamers M, Kishimoto T, Zinkernagel R, Bluethmann H, Kohler G: Impaired immune and acute-phase responses in interleukin-6-deficient mice. Nature 1994, 368:339–342.CrossRefPubMed

18.

Fattori E, Cappelletti M, Costa P, Sellitto C, Cantoni L, Carelli M, Faggioni R, Fantuzzi G, Ghezzi P, Poli V: Defective inflammatory response in interleukin 6-deficient mice. J Exp Med 1994, 180:1243–1250.CrossRefPubMed

19.

Xing Z, Gauldie J, Cox G, Baumann H, Jordana M, Lei XF, Achong MK: IL-6 is an antiinflammatory cytokine required for controlling local or systemic acute inflammatory responses. J Clin Invest 1998, 101:311–320.CrossRefPubMedPubMedCentral

20.

Pardanani A, Hood J, Lasho T, Levine RL, Martin MB, Noronha G, Finke C, Mak CC, Mesa R, Zhu H, Soll R, Gilliland DG, Tefferi A: TG101209, a small molecule JAK2-selective kinase inhibitor potently inhibits myeloproliferative disorder-associated JAK2V617F and MPLW515L/K mutations. Leukemia 2007, 21:1658–1668.CrossRefPubMed

21.

Ramakrishnan V, Kimlinger T, Haug J, Timm M, Wellik L, Halling T, Pardanani A, Tefferi A, Rajkumar SV, Kumar S: TG101209, a novel JAK2 inhibitor, has significant in vitro activity in multiple myeloma and displays preferential cytotoxicity for CD45+ myeloma cells. Am J Hematol 2010, 85:675–686.CrossRefPubMedPubMedCentral

22.

Wang Y, Fiskus W, Chong DG, Buckley KM, Natarajan K, Rao R, Joshi A, Balusu R, Koul S, Chen J, Savoie A, Ustun C, Jillella AP, Atadja P, Levine RL, Bhalla KN: Cotreatment with panobinostat and JAK2 inhibitor TG101209 attenuates JAK2V617F levels and signaling and exerts synergistic cytotoxic effects against human myeloproliferative neoplastic cells. Blood 2009, 114:5024–5033.CrossRefPubMedPubMedCentral

23.

Sun Y, Moretti L, Giacalone NJ, Schleicher S, Speirs CK, Carbone DP, Lu B: Inhibition of JAK2 signaling by TG101209 enhances radiotherapy in lung cancer models. J Thorac Oncol 2011, 6:699–706.CrossRefPubMedPubMedCentral

24.

Manderson AP, Kay JG, Hammond LA, Brown DL, Stow JL: Subcompartments of the macrophage recycling endosome direct the differential secretion of IL-6 and TNFalpha. J Cell Biol 2007, 178:57–69.CrossRefPubMedPubMedCentral

25.

Wallach D, Varfolomeev EE, Malinin NL, Goltsev YV, Kovalenko AV, Boldin MP: Tumor necrosis factor receptor and Fas signaling mechanisms. Annu Rev Immunol 1999, 17:331–367.CrossRefPubMed

26.

Baud V, Karin M: Signal transduction by tumor necrosis factor and its relatives. Trends Cell Biol 2001, 11:372–377.CrossRefPubMed

27.

Hehlgans T, Pfeffer K: The intriguing biology of the tumour necrosis factor/tumour necrosis factor receptor superfamily: players, rules and the games. Immunology 2005, 115:1–20.CrossRefPubMedPubMedCentral

28.

Chen P, Huang L, Zhang Y, Qiao M, Yao W, Yuan Y: The antagonist of the JAK-1/STAT-1 signaling pathway improves the severity of cerulein-stimulated pancreatic injury via inhibition of NF-kappaB activity. Int J Mol Med 2011, 27:731–738.PubMed

29.

Funakoshi-Tago M, Tago K, Sato Y, Tominaga S, Kasahara T: JAK2 is an important signal transducer in IL-33-induced NF-kappaB activation. Cell Signal 2011, 23:363–370.CrossRefPubMed

30.

Qi XF, Kim DH, Yoon YS, Jin D, Huang XZ, Li JH, Deung YK, Lee KJ: Essential involvement of cross-talk between IFN-gamma and TNF-alpha in CXCL10 production in human THP-1 monocytes. J Cell Physiol 2009, 220:690–697.CrossRefPubMed

31.

Gearing AJ, Beckett P, Christodoulou M, Churchill M, Clements JM, Crimmin M, Davidson AH, Drummond AH, Galloway WA, Gilbert R, Gordon JL, Leber TM, Mangan M, Miller K, Nayee P, Owen K, Patel S, Thomas W, Wells G, Wood LM: Woolley, K:l. Matrix metalloproteinases and processing of pro-TNF-alpha. J Leukoc Biol 1995, 57:774–777.PubMed

32.

Argetsinger LS, Campbell GS, Yang X, Witthuhn BA, Silvennoinen O, Ihle JN, Carter-Su C: Identification of JAK2 as a growth hormone receptor-associated tyrosine kinase. Cell 1993, 74:237–244.CrossRefPubMed

33.

Fuortes M, Jin WW, Nathan C: Adhesion-dependent protein tyrosine phosphorylation in neutrophils treated with tumor necrosis factor. J Cell Biol 1993, 120:777–784.CrossRefPubMed

34.

Fuortes M, Jin WW, Nathan C: Beta 2 integrin-dependent tyrosine phosphorylation of paxillin in human neutrophils treated with tumor necrosis factor. J Cell Biol 1994, 127:1477–1483.CrossRefPubMed

35.

Fuortes M, Melchior M, Han H, Lyon GJ, Nathan C: Role of the tyrosine kinase pyk2 in the integrin-dependent activation of human neutrophils by TNF. J Clin Invest 1999, 104:327–335.CrossRefPubMedPubMedCentral

36.

Mishra S, Mathur R, Hamburger AW: Modulation of the cytotoxic activity of tumor necrosis factor by protein tyrosine kinase and protein tyrosine phosphatase inhibitors. Lymphokine Cytokine Res 1994, 13:77–83.PubMed

37.

Takada Y, Aggarwal BB: TNF activates Syk protein tyrosine kinase leading to TNF-induced MAPK activation, NF-kappaB activation, and apoptosis. J Immunol 2004, 173:1066–1077.CrossRefPubMed

38.

Pincheira R, Castro AF, Ozes ON, Idumalla PS, Donner DB: Type 1 TNF receptor forms a complex with and uses Jak2 and c-Src to selectively engage signaling pathways that regulate transcription factor activity. J Immunol 2008, 181:1288–1298.CrossRefPubMed

39.

Wang M, Markel T, Crisostomo P, Herring C, Meldrum KK, Lillemoe KD, Meldrum DR: Deficiency of TNFR1 protects myocardium through SOCS3 and IL-6 but not p38 MAPK or IL-1beta. Am J Physiol Heart Circ Physiol 2007, 292:H1694-H1699.CrossRefPubMed

40.

Eriksson U, Kurrer MO, Schmitz N, Marsch SC, Fontana A, Eugster HP, Kopf M: Interleukin-6-deficient mice resist development of autoimmune myocarditis associated with impaired upregulation of complement C3. Circulation 2003, 107:320–325.CrossRefPubMed

41.

Ohshima S, Saeki Y, Mima T, Sasai M, Nishioka K, Nomura S, Kopf M, Katada Y, Tanaka T, Suemura M, Kishimoto T: Interleukin 6 plays a key role in the development of antigen-induced arthritis. Proc Natl Acad Sci U S A 1998, 95:8222–8226.CrossRefPubMedPubMedCentral

42.

Alonzi T, Fattori E, Lazzaro D, Costa P, Probert L, Kollias G, De Benedetti F, Poli V, Ciliberto G: Interleukin 6 is required for the development of collagen-induced arthritis. J Exp Med 1998, 187:461–468.CrossRefPubMedPubMedCentral

43.

Deng C, Goluszko E, Tuzun E, Yang H, Christadoss P: Resistance to experimental autoimmune myasthenia gravis in IL-6-deficient mice is associated with reduced germinal center formation and C3 production. J Immunol 2002, 169:1077–1083.CrossRefPubMed

44.

Tilg H, Trehu E, Atkins MB, Dinarello CA, Mier JW: Interleukin-6 (IL-6) as an anti-inflammatory cytokine: induction of circulating IL-1 receptor antagonist and soluble tumor necrosis factor receptor p55. Blood 1994, 83:113–118.PubMed

45.

Yasukawa H, Ohishi M, Mori H, Murakami M, Chinen T, Aki D, Hanada T, Takeda K, Akira S, Hoshijima M, Hirano T, Chien KR, Yoshimura A: IL-6 induces an anti-inflammatory response in the absence of SOCS3 in macrophages. Nat Immunol 2003, 4:551–556.CrossRefPubMed

46.

Lynch AM, Walsh C, Delaney A, Nolan Y, Campbell VA, Lynch MA: Lipopolysaccharide-induced increase in signalling in hippocampus is abrogated by IL-10–a role for IL-1 beta? J Neurochem 2004, 88:635–646.CrossRefPubMed

Title: LPS-induced release of IL-6 from glia modulates production of IL-1β in a JAK2-dependent manner
Authors: Aedín M Minogue
James P Barrett
Marina A Lynch
Publication date: 01-12-2012
Publisher: BioMed Central
Published in: Journal of Neuroinflammation / Issue 1/2012
Electronic ISSN: 1742-2094
DOI: https://doi.org/10.1186/1742-2094-9-126

Keynote webinar | Spotlight on medication adherence

Springer Medicine

LPS-induced release of IL-6 from glia modulates production of IL-1β in a JAK2-dependent manner

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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