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

Overview

Journal PLoS Pathog

Specialty Microbiology

Date 2010 Nov 19

PMID 21085614

Citations 45

Authors

Mashael S Al-Mutairi

Laurence C Cadalbert

H Adrienne McGachy

Muhannad Shweash

Juliane Schroeder

Magdalena Kurnik

Callum M Sloss

Clare E Bryant

James Alexander

Robin Plevin

Affiliations

Soon will be listed here.

Abstract

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 PGE(2) 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.

Citing Articles

Mitogen-Activated Protein Kinase Phosphatase-2 Deletion Promotes Hyperglycemia and Susceptibility to Streptozotocin-Induced Diabetes in Female Mice In Vivo.

Ghimire N, Welch M, Secunda C, Fink A, Lawan A Cells. 2025; 14(4).

PMID: 39996734 PMC: 11853640. DOI: 10.3390/cells14040261.

The vertebrate segmentation clock drives segmentation by stabilizing Dusp phosphatases in zebrafish.

Simsek M, Saparov D, Keseroglu K, Zinani O, Chandel A, Dulal B Dev Cell. 2024; 60(5):669-678.e6.

PMID: 39610242 PMC: 11903174. DOI: 10.1016/j.devcel.2024.11.003.

DUSP4 modulates RIG-I- and STING-mediated IRF3-type I IFN response.

Jiao H, James S, Png C, Cui C, Li H, Li L Cell Death Differ. 2024; 31(3):280-291.

PMID: 38383887 PMC: 10923883. DOI: 10.1038/s41418-024-01269-7.

Dual-Specificity Phosphatases in Regulation of Tumor-Associated Macrophage Activity.

Patysheva M, Prostakishina E, Budnitskaya A, Bragina O, Kzhyshkowska J Int J Mol Sci. 2023; 24(24).

PMID: 38139370 PMC: 10743672. DOI: 10.3390/ijms242417542.

Cereblon influences the timing of muscle differentiation in tadpoles.

Long J, Mariossi A, Cao C, Mo Z, Thompson J, Levine M Proc Natl Acad Sci U S A. 2023; 120(43):e2309989120.

PMID: 37856545 PMC: 10614628. DOI: 10.1073/pnas.2309989120.

References

Robinson C, Sloss C, Plevin R . 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. 2001; 13(1):29-41. DOI: 10.1016/s0898-6568(00)00121-2. View

Naderer T, McConville M . The Leishmania-macrophage interaction: a metabolic perspective. Cell Microbiol. 2007; 10(2):301-8. DOI: 10.1111/j.1462-5822.2007.01096.x. View

Keyse S . Dual-specificity MAP kinase phosphatases (MKPs) and cancer. Cancer Metastasis Rev. 2008; 27(2):253-61. DOI: 10.1007/s10555-008-9123-1. View

Satoskar A, Brombacher F, Dai W, McInnes I, Liew F, Alexander J . SCID mice reconstituted with IL-4-deficient lymphocytes, but not immunocompetent lymphocytes, are resistant to cutaneous leishmaniasis. J Immunol. 1997; 159(10):5005-13. View

Tresini M, Lorenzini A, Torres C, Cristofalo V . Modulation of replicative senescence of diploid human cells by nuclear ERK signaling. J Biol Chem. 2006; 282(6):4136-51. DOI: 10.1074/jbc.M604955200. View

Jeffrey K, Brummer T, Rolph M, Liu S, Callejas N, Grumont R . Positive regulation of immune cell function and inflammatory responses by phosphatase PAC-1. Nat Immunol. 2006; 7(3):274-83. DOI: 10.1038/ni1310. View

Zhang Y, Blattman J, Kennedy N, Duong J, Nguyen T, Wang Y . Regulation of innate and adaptive immune responses by MAP kinase phosphatase 5. Nature. 2004; 430(7001):793-7. DOI: 10.1038/nature02764. View

Yang Z, Mosser D, Zhang X . Activation of the MAPK, ERK, following Leishmania amazonensis infection of macrophages. J Immunol. 2007; 178(2):1077-85. PMC: 2643020. DOI: 10.4049/jimmunol.178.2.1077. View

Fiebich B, Akundi R, Biber K, Hamke M, Schmidt C, Butcher R . 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. 2005; 46(6):501-12. DOI: 10.1016/j.neuint.2004.11.009. View

10.

Kinney C, Chandrasekharan U, Yang L, Shen J, Kinter M, McDermott M . Histone H3 as a novel substrate for MAP kinase phosphatase-1. Am J Physiol Cell Physiol. 2008; 296(2):C242-9. PMC: 2643854. DOI: 10.1152/ajpcell.00492.2008. View

11.

Chu Y, Solski P, Khosravi-Far R, Der C, Kelly K . 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. 1996; 271(11):6497-501. DOI: 10.1074/jbc.271.11.6497. View

12.

Sieben N, Oosting J, Flanagan A, Prat J, Roemen G, Kolkman-Uljee S . 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. 2005; 23(29):7257-64. DOI: 10.1200/JCO.2005.02.2541. View

13.

Guo X, Gerl R, Schrader J . 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. 2003; 278(25):22237-42. DOI: 10.1074/jbc.M300847200. View

14.

Salojin K, Owusu I, Millerchip K, Potter M, Platt K, Oravecz T . Essential role of MAPK phosphatase-1 in the negative control of innate immune responses. J Immunol. 2006; 176(3):1899-907. DOI: 10.4049/jimmunol.176.3.1899. View

15.

Buxbaum L, Denise H, Coombs G, Alexander J, Mottram J, Scott P . Cysteine protease B of Leishmania mexicana inhibits host Th1 responses and protective immunity. J Immunol. 2003; 171(7):3711-7. DOI: 10.4049/jimmunol.171.7.3711. View

16.

Munder M, Mollinedo F, Calafat J, Canchado J, Gil-Lamaignere C, Fuentes J . Arginase I is constitutively expressed in human granulocytes and participates in fungicidal activity. Blood. 2004; 105(6):2549-56. DOI: 10.1182/blood-2004-07-2521. View

17.

Pollock K, Conacher M, Wei X, Alexander J, Brewer J . 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. 2003; 108(2):137-43. PMC: 1782874. DOI: 10.1046/j.1365-2567.2003.01581.x. View

18.

Nelin L, Wang X, Zhao Q, Chicoine L, Young T, Hatch D . MKP-1 switches arginine metabolism from nitric oxide synthase to arginase following endotoxin challenge. Am J Physiol Cell Physiol. 2007; 293(2):C632-40. DOI: 10.1152/ajpcell.00137.2006. View

19.

Furst R, Schroeder T, Eilken H, Bubik M, Kiemer A, Zahler S . MAPK phosphatase-1 represents a novel anti-inflammatory target of glucocorticoids in the human endothelium. FASEB J. 2006; 21(1):74-80. DOI: 10.1096/fj.06-6752com. View

20.

Chi H, Barry S, Roth R, Wu J, Jones E, Bennett A . 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. 2006; 103(7):2274-9. PMC: 1413743. DOI: 10.1073/pnas.0510965103. View