Activation of the JNK signalling pathway by macrophage migration inhibitory factor (MIF) and dependence on CXCR4 and CD74.
c-Jun N-terminal kinase (JNK) is a member of the mitogen-activated protein kinase (MAPK) family and controls essential processes such as inflammation, cell differentiation, and apoptosis. JNK signalling is triggered by extracellular signals such as cytokines and environmental stresses. Macrophage migration inhibitory factor (MIF) is a pleiotropic pro-inflammatory cytokine with chemokine-like functions in leukocyte recruitment and atherosclerosis. MIF promotes MAPK signalling through ERK1/2, while it can either activate or inhibit JNK phosphorylation, depending on the cell type and underlying stimulation context. MIF activities are mediated by non-cognate interactions with the CXC chemokine receptors CXCR2 and CXCR4 or by ligation of CD74, which is the cell surface expressed form of the class II invariant chain. ERK1/2 signalling stimulated by MIF is dependent on CD74, but the receptor pathway involved in MIF activation of the JNK pathway is unknown. Here we comprehensively characterize the stimulatory effect of MIF on the canonical JNK/c-Jun/AP-1 pathway in fibroblasts and T cell lines and identify the upstream signalling components. Physiological concentrations of recombinant MIF triggered the phosphorylation of JNK and c-Jun and rapidly activated AP-1. In T cells, MIF-mediated activation of the JNK pathway led to upregulated gene expression of the inflammatory chemokine CXCL8. Activation of JNK signalling by MIF involved the upstream kinases PI3K and SRC and was found to be dependent on CXCR4 and CD74. Together, these data show that the CXCR4/CD74/SRC/PI3K axis mediates a rapid and transient activation of the JNK pathway as triggered by the inflammatory cytokine MIF in T cells and fibroblasts.
Lue
Hongqi
H
Institute of Biochemistry and Molecular Cell Biology, RWTH Aachen University, Pauwelsstrasse 30, Aachen, Germany.
Dewor
Manfred
M
Leng
Lin
L
Bucala
Richard
R
Bernhagen
Jürgen
J
D000818:Animals; D000944:Antigens, Differentiation, B-Lymphocyte / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D005347:Fibroblasts / Q000378:metabolism; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008263:Macrophage Migration-Inhibitory Factors / Q000378:metabolism*; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism
D000944:Antigens, Differentiation, B-Lymphocyte; D000949:Histocompatibility Antigens Class II; D016209:Interleukin-8; D008263:Macrophage Migration-Inhibitory Factors; D034741:RNA, Small Interfering; D019718:Receptors, CXCR4; D018808:Transcription Factor AP-1; C045084:invariant chain; D019869:Phosphatidylinositol 3-Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3
Proc Natl Acad Sci U S A. 2002 Jan 8;99(1):345-50
11756671
Cell Signal. 2006 May;18(5):688-703
16122907
Exp Cell Res. 2007 Nov 15;313(19):4051-65
17706641
J Biol Chem. 2004 Jan 16;279(3):1676-83
14581488
Biochem Biophys Res Commun. 2008 Jun 27;371(2):298-303
18439909
J Neurooncol. 2007 Aug;84(1):21-9
17415525
Bioessays. 2006 Sep;28(9):923-34
16937364
Biochim Biophys Acta. 2010 Mar;1804(3):463-75
19900593
J Immunol. 2008 Aug 15;181(4):2330-7
18684922
Semin Cancer Biol. 2000 Oct;10(5):359-66
11100884
Nature. 2000 Nov 9;408(6809):211-6
11089976
Kidney Int. 1997 Mar;51(3):631-9
9067893
J Immunol. 2003 Mar 15;170(6):3337-47
12626594
Eur J Immunol. 2006 May;36(5):1285-95
16619289
Sci STKE. 2000 Jul 11;2000(40):re1
11752597
Proc Natl Acad Sci U S A. 2007 Aug 14;104(33):13408-13
17686984
Biochem Biophys Res Commun. 2007 Jul 13;358(4):990-6
17521613
FEBS Lett. 1997 Sep 8;414(2):226-32
9315691
Nat Rev Drug Discov. 2006 May;5(5):399-410
16628200
Circulation. 2004 Jan 27;109(3):380-5
14691040
Immunity. 2006 Oct;25(4):595-606
17045821
Biochim Biophys Acta. 2007 Apr;1768(4):952-63
17169327
EMBO J. 1996 Jun 3;15(11):2760-70
8654373
Proc Natl Acad Sci U S A. 2003 Aug 5;100(16):9354-9
12878730
Nat Med. 2007 May;13(5):587-96
17435771
Nature. 2000 Nov 9;408(6809):146-7
11089953
Int J Cancer. 2009 Feb 15;124(4):853-61
19035451
J Clin Invest. 2009 Dec;119(12):3807-16
19920350
FEBS Lett. 2009 Sep 3;583(17):2749-57
19665027
J Leukoc Biol. 2001 Jan;69(1):3-10
11200064
FEBS Lett. 2003 Sep 11;551(1-3):78-86
12965208
Nature. 1995 Sep 7;377(6544):68-71
7659164
J Neurochem. 2003 May;85(4):1064-74
12716438
J Immunol. 2006 Jun 1;176(11):6794-801
16709839
Nat Med. 2000 Feb;6(2):164-70
10655104
J Interferon Cytokine Res. 2007 Feb;27(2):103-9
17316137
Oncogene. 2007 Aug 2;26(35):5046-59
17310986
Front Biosci. 2008 May 01;13:6820-33
18508696
J Neuroimmunol. 2006 Aug;177(1-2):27-39
16782208
Haematologica. 2008 Apr;93(4):524-32
18322253
Nat Med. 1997 Mar;3(3):320-3
9055860
Nat Rev Immunol. 2003 Oct;3(10):791-800
14502271
Arthritis Res Ther. 2006;8(4):R132
16872482
J Biol Chem. 1999 Jun 18;274(25):18100-6
10364264
Nature. 1993 Oct 21;365(6448):756-9
8413654
Nature. 2001 Mar 1;410(6824):37-40
11242034
Eur J Immunol. 1997 Aug;27(8):2102-12
9295051
Nat Rev Cancer. 2009 Aug;9(8):537-49
19629069
Annu Rev Cell Dev Biol. 2003;19:91-118
14570565
Sci Signal. 2010 Jan 19;3(105):cm2
20086236
Eur J Biochem. 2000 Dec;267(24):7183-93
11106430
J Immunol. 2009 Jun 1;182(11):6896-906
19454686
Curr Opin Cell Biol. 1998 Apr;10(2):205-19
9561845
J Exp Med. 2003 Jun 2;197(11):1467-76
12782713
Shock. 2005 Dec;24(6):556-63
16317387
N Engl J Med. 2006 Feb 9;354(6):610-21
16467548
J Biol Chem. 2005 Jul 15;280(28):26263-77
15890643
J Biol Chem. 2002 Jun 14;277(24):21325-31
11925444
Cell. 2000 Oct 13;103(2):239-52
11057897
Circulation. 2008 Mar 25;117(12):1594-602
18362243
Microbes Infect. 2002 Apr;4(4):449-60
11932196
J Biol Chem. 2002 Mar 8;277(10):7865-74
11751895
J Biol Chem. 2003 Sep 5;278(36):33654-71
12796500