MAP Kinase Phosphatase-2 Plays a Critical Role in Response to Infection by

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In this study we generated a novel dual specific phosphatase 4 (DUSP4) deletion mouse using a targeted deletion strategy in order to examine the role of MAP kinase phosphatase-2 (MKP-2) in immune responses. Lipopolysaccharide (LPS) induced a rapid, time and concentration-dependent increase in MKP-2 protein expression in bone marrow-derived macrophages from MKP-2^+/+ but not from MKP-2^−/− mice. LPS-induced JNK and p38 MAP kinase phosphorylation was significantly increased and prolonged in MKP-2^−/− macrophages whilst ERK phosphorylation was unaffected. MKP-2 deletion also potentiated LPS-stimulated induction of the inflammatory cytokines, IL-6, IL-12p40, TNF-α, and also COX-2 derived PGE₂ production. However surprisingly, in MKP-2^−/− macrophages, there was a marked reduction in LPS or IFNγ-induced iNOS and nitric oxide release and enhanced basal expression of arginase-1, suggesting that MKP-2 may have an additional regulatory function significant in pathogen-mediated immunity. Indeed, following infection with the intracellular parasite Leishmania mexicana, MKP-2^−/− mice displayed increased lesion size and parasite burden, and a significantly modified Th1/Th2 bias compared with wild-type counterparts. However, there was no intrinsic defect in MKP-2^−/− T cell function as measured by anti-CD3 induced IFN-γ production. Rather, MKP-2^−/− bone marrow-derived macrophages were found to be inherently more susceptible to infection with Leishmania mexicana, an effect reversed following treatment with the arginase inhibitor nor-NOHA. These findings show for the first time a role for MKP-2 in vivo and demonstrate that MKP-2 may be essential in orchestrating protection against intracellular infection at the level of the macrophage.

Vyšlo v časopise: MAP Kinase Phosphatase-2 Plays a Critical Role in Response to Infection by. PLoS Pathog 6(11): e32767. doi:10.1371/journal.ppat.1001192
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1001192

Souhrn

Zdroje

1. KeyseSM

2008 Dual-specificity MAP kinase phosphatases (MKPs) and cancer. Cancer Metastasis Rev 27 253 261

2. WuJJ

RothRJ

AndersonEJ

HongEG

LeeMK

2006 Mice lacking MAP kinase phosphatase-1 have enhanced MAP kinase activity and resistance to diet-induced obesity. Cell Metab 4 61 73

3. XuH

YangQ

ShenM

HuangX

DembskiM

2005 Dual specificity MAPK phosphatase 3 activates PEPCK gene transcription and increases gluconeogenesis in rat hepatoma cells. J Biol Chem 280 36013 36018

4. HammerM

MagesJ

DietrichH

ServatiusA

HowellsN

2006 Dual specificity phosphatase 1 (DUSP1) regulates a subset of LPS-induced genes and protects mice from lethal endotoxin shock. J Exp Med 203 15 20

5. ZhaoQ

WangX

NelinLD

YaoY

MattaR

2006 MAP kinase phosphatase 1 controls innate immune responses and suppresses endotoxic shock. J Exp Med 203 131 140

6. JeffreyKL

BrummerT

RolphMS

LiuSM

CallejasNA

2006 Positive regulation of immune cell function and inflammatory responses by phosphatase PAC-1. Nat Immunol 7 274 283

7. ZhangY

BlattmanJN

KennedyNJ

DuongJ

NguyenT

2004 Regulation of innate and adaptive immune responses by MAP kinase phosphatase 5. Nature 430 793 797

8. FurstR

SchroederT

EilkenHM

BubikMF

KiemerAK

2007 MAPK phosphatase-1 represents a novel anti-inflammatory target of glucocorticoids in the human endothelium. Faseb J 21 74 80

9. Misra-PressA

RimCS

YaoH

RobersonMS

StorkPJ

1995 A novel mitogen-activated protein kinase phosphatase. Structure, expression, and regulation. J Biol Chem 270 14587 14596

10. SlossCM

CadalbertL

FinnSG

FullerSJ

PlevinR

2005 Disruption of two putative nuclear localization sequences is required for cytosolic localization of mitogen-activated protein kinase phosphatase-2. Cell Signal 17 709 716

11. ChuY

SolskiPA

Khosravi-FarR

DerCJ

KellyK

1996 The mitogen-activated protein kinase phosphatases PAC1, MKP-1, and MKP-2 have unique substrate specificities and reduced activity in vivo toward the ERK2 sevenmaker mutation. J Biol Chem 271 6497 6501

12. ChenP

HutterD

YangX

GorospeM

DavisRJ

2001 Discordance between the binding affinity of mitogen-activated protein kinase subfamily members for MAP kinase phosphatase-2 and their ability to activate the phosphatase catalytically. J Biol Chem 276 29440 29449

13. CadalbertL

SlossCM

CameronP

PlevinR

2005 Conditional expression of MAP kinase phosphatase-2 protects against genotoxic stress-induced apoptosis by binding and selective dephosphorylation of nuclear activated c-jun N-terminal kinase. Cell Signal 17 1254 1264

14. RobinsonCJ

SlossCM

PlevinR

2001 Inactivation of JNK activity by mitogen-activated protein kinase phosphatase-2 in EAhy926 endothelial cells is dependent upon agonist-specific JNK translocation to the nucleus. Cell Signal 13 29 41

15. TresiniM

LorenziniA

TorresC

CristofaloVJ

2007 Modulation of replicative senescence of diploid human cells by nuclear ERK signaling. J Biol Chem 282 4136 4151

16. SiebenNL

OostingJ

FlanaganAM

PratJ

RoemenGM

2005 Differential gene expression in ovarian tumors reveals Dusp 4 and Serpina 5 as key regulators for benign behavior of serous borderline tumors. J Clin Oncol 23 7257 7264

17. ForgetG

GregoryDJ

WhitcombeLA

OlivierM

2006 Role of host protein tyrosine phosphatase SHP-1 in Leishmania donovani-induced inhibition of nitric oxide production. Infect Immun 74 6272 6279

18. NadererT

McConvilleMJ

2008 The Leishmania-macrophage interaction: a metabolic perspective. Cell Microbiol 10 301 308

19. WeiXQ

CharlesIG

SmithA

UreJ

FengGJ

1995 Altered immune responses in mice lacking inducible nitric oxide synthase. Nature 375 408 411

20. YangZ

MosserDM

ZhangX

2007 Activation of the MAPK, ERK, following Leishmania amazonensis infection of macrophages. J Immunol 178 1077 1085

21. ModolellM

ChoiBS

RyanRO

HancockM

TitusRG

2009 Local suppression of T cell responses by arginase-induced L-arginine depletion in nonhealing leishmaniasis. PLoS Negl Trop Dis 3 e480

22. MunderM

MollinedoF

CalafatJ

CanchadoJ

Gil-LamaignereC

2005 Arginase I is constitutively expressed in human granulocytes and participates in fungicidal activity. Blood 105 2549 2556

23. BuxbaumLU

DeniseH

CoombsGH

AlexanderJ

MottramJC

2003 Cysteine protease B of Leishmania mexicana inhibits host Th1 responses and protective immunity. J Immunol 171 3711 3717

24. McMahon-PrattD

AlexanderJ

2004 Does the Leishmania major paradigm of pathogenesis and protection hold for New World cutaneous leishmaniases or the visceral disease? Immunol Rev 201 206 224

25. BerasiSP

HuardC

LiD

ShihHH

SunY

2006 Inhibition of Gluconeogenesis through Transcriptional Activation of EGR1 and DUSP4 by AMP-activated Kinase. J Biol Chem 281 27167 27177

26. SalojinKV

OwusuIB

MillerchipKA

PotterM

PlattKA

2006 Essential role of MAPK phosphatase-1 in the negative control of innate immune responses. J Immunol 176 1899 1907

27. FiebichBL

AkundiRS

BiberK

HamkeM

SchmidtC

2005 IL-6 expression induced by adenosine A2b receptor stimulation in U373 MG cells depends on p38 mitogen activated kinase and protein kinase C. Neurochem Int 46 501 512

28. GuoX

GerlRE

SchraderJW

2003 Defining the involvement of p38alpha MAPK in the production of anti- and proinflammatory cytokines using an SB 203580-resistant form of the kinase. J Biol Chem 278 22237 22242

29. KrauseA

HoltmannH

EickemeierS

WinzenR

SzamelM

1998 Stress-activated protein kinase/Jun N-terminal kinase is required for interleukin (IL)-1-induced IL-6 and IL-8 gene expression in the human epidermal carcinoma cell line KB. J Biol Chem 273 23681 23689

30. ChiH

BarrySP

RothRJ

WuJJ

JonesEA

2006 Dynamic regulation of pro- and anti-inflammatory cytokines by MAPK phosphatase 1 (MKP-1) in innate immune responses. Proc Natl Acad Sci U S A 103 2274 2279

31. NelinLD

WangX

ZhaoQ

ChicoineLG

YoungTL

2007 MKP-1 switches arginine metabolism from nitric oxide synthase to arginase following endotoxin challenge. Am J Physiol Cell Physiol 293 C632 640

32. WangX

MengX

KuhlmanJR

NelinLD

NicolKK

2007 Knockout of Mkp-1 enhances the host inflammatory responses to gram-positive bacteria. J Immunol 178 5312 5320

33. KinneyCM

ChandrasekharanUM

YangL

ShenJ

KinterM

2009 Histone H3 as a novel substrate for MAP kinase phosphatase-1. Am J Physiol Cell Physiol 296 C242 249

34. ConstantSL

DongC

YangDD

WyskM

DavisRJ

2000 JNK1 is required for T cell-mediated immunity against Leishmania major infection. J Immunol 165 2671 2676

35. El KasmiKC

QuallsJE

PesceJT

SmithAM

ThompsonRW

2008 Toll-like receptor-induced arginase 1 in macrophages thwarts effective immunity against intracellular pathogens. Nat Immunol 9 1399 1406

36. GaurU

RobertsSC

DalviRP

CorralizaI

UllmanB

2007 An effect of parasite-encoded arginase on the outcome of murine cutaneous leishmaniasis. J Immunol 179 8446 8453

37. RobertsSC

TancerMJ

PolinskyMR

GibsonKM

HebyO

2004 Arginase plays a pivotal role in polyamine precursor metabolism in Leishmania. Characterization of gene deletion mutants. J Biol Chem 279 23668 23678

38. SatoskarA

BrombacherF

DaiWJ

McInnesI

LiewFY

1997 SCID mice reconstituted with IL-4-deficient lymphocytes, but not immunocompetent lymphocytes, are resistant to cutaneous leishmaniasis. J Immunol 159 5005 5013

39. PollockKG

ConacherM

WeiXQ

AlexanderJ

BrewerJM

2003 Interleukin-18 plays a role in both the alum-induced T helper 2 response and the T helper 1 response induced by alum-adsorbed interleukin-12. Immunology 108 137 143