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Aging and Disease    2010, Vol. 1 Issue (3) : 199-211     DOI:
The p38 MAP Kinase Family as Regulators of Proinflammatory Cytokine Production in Degenerative Diseases of the CNS
Adam D. Bachstetter1, Linda J. Van Eldik1, 2, *
1Sanders-Brown Center on Aging
2Dept Anatomy and Neurobiology, University of Kentucky Lexington, KY 40536-0230 USA
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Inflammation in the central nervous system (CNS) is a common feature of age-related neurodegenerative diseases. Proinflammatory cytokines, such as IL-1β and TNFα, are produced primarily by cells of the innate immune system, namely microglia in the CNS, and are believed to contribute to the neuronal damage seen in the disease. The p38 mitogen-activated protein kinase (MAPK) is one of the kinase pathways that regulate the production of IL-1β and TNFα. Importantly, small molecule inhibitors of the p38 MAPK family have been developed and show efficacy in blocking the production of IL-1β and TNFα. The p38 family consists of at least four isoforms (p38α, β, γ, δ) encoded by separate genes. Recent studies have begun to demonstrate unique functions of the different isoforms, with p38α being implicated as the key isoform involved in CNS inflammation. Interestingly, there is also emerging evidence that two downstream substrates of p38 may have opposing roles, with MK2 being pro-inflammatory and MSK1/2 being antiinflammatory. This review discusses the properties, function and regulation of the p38 MAPK family as it relates to cytokine production in the CNS.

Keywords Protein kinase      Neuroinflammation      Neurodegeneration      Microglia      Signal Transduction     
Corresponding Authors: Linda J. Van Eldik   
Issue Date: 01 March 2010
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Adam D. Bachstetter,Linda J. Van Eldik. The p38 MAP Kinase Family as Regulators of Proinflammatory Cytokine Production in Degenerative Diseases of the CNS[J]. Aging and Disease, 2010, 1(3): 199-211.
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[1] Van Eldik LJ, Thompson WL, Ralay Ranaivo H, Behanna HA, Watterson DM(2007). Glia proinflammatory cytokine upregulation as a therapeutic target for neurodegenerative diseases: function-based and target-based discovery approaches. Int Rev Neurobiol, 82:277-96
[2] Raingeaud J, Gupta S, Rogers JS, Dickens M, Han J, Ulevitch RJ, Davis RJ(1995). Pro-inflammatory cytokines and environmental stress cause p38 mitogen-activated protein kinase activation by dual phosphorylation on tyrosine and threonine. J Biol Chem, 270:7420-6
[3] Rouse J, Cohen P, Trigon S, Morange M, Alonso-Llamazares A, Zamanillo D, Hunt, Nebreda AR(1994). A novel kinase cascade triggered by stress and heat shock that stimulates MAPKAP kinase-2 and phosphorylation of the small heat shock proteins. Cell, 78:1027-37
[4] Freshney NW, Rawlinson L, Guesdon F, Jones E, Cowley S, Hsuan J, Saklatvala J(1994). Interleukin-1 activates a novel protein kinase cascade that results in the phosphorylation of Hsp27. Cell, 78:1039-49
[5] Han J, Lee JD, Bibbs L, Ulevitch RJ(1994). A MAP kinase targeted by endotoxin and hyperosmolarity in mammalian cells. Science, 265:808-11
[6] Han J, Lee JD, Tobias PS, Ulevitch RJ(1993). Endotoxin induces rapid protein tyrosine phosphorylation in 70Z/3 cells expressing CD14. J Biol Chem, 268:25009-14
[7] Schieven GL(2009). The p38alpha kinase plays a central role in inflammation. Curr Top Med Chem, 9:1038-48
[8] Jiang Y, Chen C, Li Z, Guo W, Gegner JA, Lin S, Han J(1996). Characterization of the structure and function of a new mitogen-activated protein kinase (p38beta)J Biol Chem, 271:17920-6
[9] Li Z, Jiang Y, Ulevitch RJ, Han J(1996). The primary structure of p38 gamma: a new member of p38 group of MAP kinases. Biochem Biophys Res Commun, 228:334-40
[10] Stein B, Yang MX, Young DB, Janknecht R, Hunter T, Murray BW, Barbosa MS(1997). p38-2, a novel mitogen-activated protein kinase with distinct properties. J Biol Chem, 272:19509-17
[11] Tamura K, Sudo T, Senftleben U, Dadak AM, Johnson R, Karin M(2000). Requirement for p38alpha in erythropoietin expression: a role for stress kinases in erythropoiesis. Cell, 102:221-31
[12] Allen M, Svensson L, Roach M, Hambor J, McNeish J, Gabel CA(2000). Deficiency of the stress kinase p38alpha results in embryonic lethality: characterization of the kinase dependence of stress responses of enzyme-deficient embryonic stem cells. J Exp Med, 191:859-70
[13] Mudgett JS, Ding J, Guh-Siesel L, Chartrain NA, Yang L, Gopal S, Shen MM(2000). Essential role for p38alpha mitogen-activated protein kinase in placental angiogenesis. Proc Natl Acad Sci U S A, 97:10454-9
[14] Adams RH(2000). Essential role of p38alpha MAP kinase in placental but not embryonic cardiovascular development. Mol Cell, 6:109-16
[15] Beardmore VA(2005). Generation and characterization of p38beta (MAPK11) gene-targeted mice. Mol Cell Biol, 25:10454-64
[16] Zhang C, Kenski DM, Paulson JL, Bonshtien A, Sessa G, Cross JV, Templeton DJ, Shokat KM(2005). A second-site suppressor strategy for chemical genetic analysis of diverse protein kinases. Nat Methods, 2:435-41
[17] Lisnock J(1998). Molecular basis for p38 protein kinase inhibitor specificity. Biochemistry, 37:16573-81
[18] O'Keefe SJ(2007). Chemical genetics define the roles of p38alpha and p38beta in acute and chronic inflammation. J Biol Chem, 282:34663-71
[19] Kang YJ, Chen J, Otsuka M, Mols J, Ren S, Wang Y, Han J(2008). Macrophage deletion of p38alpha partially impairs lipopolysaccharide-induced cellular activation. J Immunol, 180:5075-82
[20] Kim C(2008). The kinase p38 alpha serves cell type-specific inflammatory functions in skin injury and coordinates pro- and anti-inflammatory gene expression. Nat Immunol, 9:1019-27
[21] Liu Y, Shepherd EG, Nelin LD(2007). MAPK phosphatases--regulating the immune response. Nat Rev Immunol, 7:202-12
[22] Zhao Q, Shepherd EG, Manson ME, Nelin LD, Sorokin A, Liu Y(2005). The role of mitogen-activated protein kinase phosphatase-1 in the response of alveolar macrophages to lipopolysaccharide: attenuation of proinflammatory cytokine biosynthesis via feedback control of p38. J Biol Chem, 280:8101-8
[23] Zhao Q(2006). MAP kinase phosphatase 1 controls innate immune responses and suppresses endotoxic shock. J Exp Med, 203:131-40
[24] Legos JJ, Erhardt JA, White RF, Lenhard SC, Chandra S, Parsons AA, Tuma RF, Barone FC(2001). SB 239063, a novel p38 inhibitor, attenuates early neuronal injury following ischemia. Brain Res, 892:70-7
[25] Barone FC(2001). SB 239063, a second-generation p38 mitogen-activated protein kinase inhibitor, reduces brain injury and neurological deficits in cerebral focal ischemia. J Pharmacol Exp Ther, 296:312-21
[26] Munoz L(2007). A novel p38 alpha MAPK inhibitor suppresses brain proinflammatory cytokine up-regulation and attenuates synaptic dysfunction and behavioral deficits in an Alzheimer's disease mouse model. J Neuroinflammation, 4:21
[27] Greenblatt MB The p38 MAPK pathway is essential for skeletogenesis and bone homeostasis in mice. J Clin Invest, 120:2457-73
[28] Jiang Y(1997). Characterization of the structure and function of the fourth member of p38 group mitogen-activated protein kinases, p38delta. J Biol Chem, 272:30122-8
[29] Hale KK, Trollinger D, Rihanek M, Manthey CL(1999). Differential expression and activation of p38 mitogen-activated protein kinase alpha, beta, gamma, and delta in inflammatory cell lineages. J Immunol, 162:4246-52
[30] Fearns C, Kline L, Gram H, Di Padova F, Zurini M, Han J, Ulevitch RJ(2000). Coordinate activation of endogenous p38alpha, beta, gamma, and delta by inflammatory stimuli. J Leukoc Biol, 67:705-11
[31] Conrad PW, Rust RT, Han J, Millhorn DE, Beitner-Johnson D(1999). Selective activation of p38alpha and p38gamma by hypoxia. Role in regulation of cyclin D1 by hypoxia in PC12 cells. J Biol Chem, 274:23570-6
[32] Buee-Scherrer V, Goedert M(2002). Phosphorylation of microtubule-associated protein tau by stress-activated protein kinases in intact cells. FEBS Lett, 515:151-4
[33] Feijoo C, Campbell DG, Jakes R, Goedert M, Cuenda A(2005). Evidence that phosphorylation of the microtubule-associated protein Tau by SAPK4/p38delta at Thr50 promotes microtubule assembly. J Cell Sci, 118:397-408
[34] Gaestel M(2006). MAPKAP kinases - MKs - two's company, three's a crowd. Nat Rev Mol Cell Biol, 7:120-30
[35] Kotlyarov A, Yannoni Y, Fritz S, Laass K, Telliez JB, Pitman D, Lin LL, Gaestel M(2002). Distinct cellular functions of MK2. Mol Cell Biol, 22:4827-35
[36] Kotlyarov A, Neininger A, Schubert C, Eckert R, Birchmeier C, Volk HD, Gaestel M(1999). MAPKAP kinase 2 is essential for LPS-induced TNF-alpha biosynthesis. Nat Cell Biol, 1:94-7
[37] Ronkina N(2007). The mitogen-activated protein kinase (MAPK)-activated protein kinases MK2 and MK3 cooperate in stimulation of tumor necrosis factor biosynthesis and stabilization of p38 MAPK. Mol Cell Biol, 27:170-81
[38] Neininger A(2002). MK2 targets AU-rich elements and regulates biosynthesis of tumor necrosis factor and interleukin-6 independently at different post-transcriptional levels. J Biol Chem, 277:3065-8
[39] Gorska MM(2007). MK2 controls the level of negative feedback in the NF-kappaB pathway and is essential for vascular permeability and airway inflammation. J Exp Med, 204:1637-52
[40] Culbert AA(2006). MAPK-activated protein kinase 2 deficiency in microglia inhibits pro-inflammatory mediator release and resultant neurotoxicity. Relevance to neuroinflammation in a transgenic mouse model of Alzheimer disease. J Biol Chem, 281:23658-67
[41] Thomas T, Timmer M, Cesnulevicius K, Hitti E, Kotlyarov A, Gaestel M(2008). MAPKAP kinase 2-deficiency prevents neurons from cell death by reducing neuroinflammation-relevance in a mouse model of Parkinson's disease. J Neurochem, 105:2039-52
[42] Wang X, Xu L, Wang H, Young PR, Gaestel M, Feuerstein GZ(2002). Mitogen-activated protein kinase-activated protein (MAPKAP) kinase 2 deficiency protects brain from ischemic injury in mice. J Biol Chem, 277:43968-72
[43] Ferger B, Leng A, Mura A, Hengerer B, Feldon J(2004). Genetic ablation of tumor necrosis factor-alpha (TNF-alpha) and pharmacological inhibition of TNF-synthesis attenuates MPTP toxicity in mouse striatum. J Neurochem, 89:822-33
[44] Gemma C(2007). Early inhibition of TNFalpha increases 6-hydroxydopamineinduced striatal degeneration. Brain Res, 1147:240-7
[45] Lee JC(1994). A protein kinase involved in the regulation of inflammatory cytokine biosynthesis. Nature, 372:739-46
[46] Anderson DR(2005). Aminocyanopyridine inhibitors of mitogen activated protein kinase-activated protein kinase 2 (MK-2)Bioorg Med Chem Let, 15:1587-90
[47] Wu JP(2007). The discovery of carboline analogs as potent MAPKAP-K2 inhibitors. Bioorg Med Chem Lett, 17:4664-9
[48] Goldberg DR(2008). Pyrazinoindolone inhibitors of MAPKAP-K2. Bioorg Med Chem Lett, 18:938-41
[49] Velcicky J Novel 3-aminopyrazole inhibitors of MK-2 discovered by scaffold hopping strategy. Bioorg Med Chem Lett, 20:1293-7
[50] Trujillo JI(2007). Novel tetrahydro-beta-carboline-1-carboxylic acids as inhibitors of mitogen activated protein kinase-activated protein kinase 2 (MK-2)Bioorg Med Chem Lett, 17:4657-63
[51] Chico LK, Van Eldik LJ, Watterson DM(2009). Targeting protein kinases in central nervous system disorders. Nat Rev Drug Discov, 8:892-909
[52] Arthur JS(2008). MSK activation and physiological roles. Front Biosci, 13:5866-79
[53] Wiggin GR, Soloaga A, Foster JM, Murray-Tait V, Cohen P, Arthur JS(2002). MSK1 and MSK2 are required for the mitogen- and stress-induced phosphorylation of CREB and ATF1 in fibroblasts. Mol Cell Biol, 22:2871-81
[54] Ananieva O(2008). The kinases MSK1 and MSK2 act as negative regulators of Toll-like receptor signaling. Nat Immunol, 9:1028-36
[55] Darragh J, Ananieva O, Courtney A, Elcombe S, Arthur JS MSK1 regulates the transcription of IL-1ra in response to TLR activation in macrophages. Biochem J, 425:595-602
[56] Webber KM, Smith MA, Lee HG, Harris PL, Moreira P, Perry G, Zhu X(2005). Mitogen- and stress-activated protein kinase 1: convergence of the ERK and p38 pathways in Alzheimer's disease. J Neurosci Res, 79:554-60
[57] Mosser DM, Zhang X(2008). Interleukin-10: new perspectives on an old cytokine. Immunol Rev, 226:205-18
[58] Gaestel M, Kotlyarov A, Kracht M(2009). Targeting innate immunity protein kinase signalling in inflammation. Nat Rev Drug Discov, 8:480-99
[59] Duraisamy S, Bajpai M, Bughani U, Dastidar SG, Ray A, Chopra P(2008). MK2: a novel molecular target for anti-inflammatory therapy. Expert Opin Ther Targets, 12:921-36
[60] Jeffrey KL, Camps M, Rommel C, Mackay CR(2007). Targeting dual-specificity phosphatases: manipulating MAP kinase signalling and immune responses. Nat Rev Drug Discov, 6:391-403
[61] Kim SH, Smith CJ, Van Eldik LJ(2004). Importance of MAPK pathways for microglial pro-inflammatory cytokine IL-1 beta production. Neurobiol Aging, 25:431-9
[62] Koistinaho M, Koistinaho J(2002). Role of p38 and p44/42 mitogen-activated protein kinases in microglia. Glia, 40:175-83
[63] McDonald DR, Bamberger ME, Combs CK, Landreth GE(1998). beta-Amyloid fibrils activate parallel mitogen-activated protein kinase pathways in microglia and THP1 monocytes. J Neurosci, 18:4451-60
[64] Ferrer I(2004). Stress kinases involved in tau phosphorylation in Alzheimer's disease, tauopathies and APP transgenic mice. Neurotox Res, 6:469-75
[65] Giovannini MG, Scali C, Prosperi C, Bellucci A, Vannucchi MG, Rosi S, Pepeu G, Casamenti F(2002). Beta-amyloid-induced inflammation and cholinergic hypofunction in the rat brain in vivo: involvement of the p38MAPK pathway. Neurobiol Dis, 11:257-74
[66] Savage MJ, Lin YG, Ciallella JR, Flood DG, Scott RW(2002). Activation of c-Jun N-terminal kinase and p38 in an Alzheimer's disease model is associated with amyloid deposition. J Neurosci, 22:3376-85
[67] Takuma K(2009). RAGE-mediated signaling contributes to intraneuronal transport of amyloid-beta and neuronal dysfunction. Proc Natl Acad Sci U S A, 106:20021-6
[68] Origlia N(2008). Receptor for advanced glycation end product-dependent activation of p38 mitogen-activated protein kinase contributes to amyloid-beta-mediated cortical synaptic dysfunction. J Neurosci, 28:3521-30
[69] Zhu X, Mei M, Lee HG, Wang Y, Han J, Perry G, Smith MA(2005). P38 activation mediates amyloid-beta cytotoxicity. Neurochem Res, 30:791-6
[70] Morfini GA(2009). Axonal transport defects in neurodegenerative diseases. J Neurosci, 29:12776-86
[71] Cuenda A, Rousseau S(2007). p38 MAP-kinases pathway regulation, function and role in human diseases. Biochim Biophys Acta, 1773:1358-75
[72] Ferrer I, Gomez-Isla T, Puig B, Freixes M, Ribe E, Dalfo E, Avila J(2005). Current advances on different kinases involved in tau phosphorylation, and implications in Alzheimer's disease and tauopathies. Curr Alzheimer Res, 2:3-18
[73] Peel AL, Sorscher N, Kim JY, Galvan V, Chen S, Bredesen DE(2004). Tau phosphorylation in Alzheimer's disease: potential involvement of an APP-MAP kinase complex. Neuromolecular Med, 5:205-18
[74] Dalrymple SA(2002). p38 mitogen activated protein kinase as a therapeutic target for Alzheimer's disease. J Mol Neurosci, 19:295-9
[75] Anderton BH(2001). Sites of phosphorylation in tau and factors affecting their regulation. Biochem Soc Symp, 73-80
[76] Li Y, Liu L, Barger SW, Griffin WS(2003). Interleukin-1 mediates pathological effects of microglia on tau phosphorylation and on synaptophysin synthesis in cortical neurons through a p38-MAPK pathway. J Neurosci, 23:1605-11
[77] Sun A, Liu M, Nguyen XV, Bing G(2003). P38 MAP kinase is activated at early stages in Alzheimer's disease brain. Exp Neurol, 183:394-405
[78] Pei JJ, Braak E, Braak H, Grundke-Iqbal I, Iqbal K, Winblad B, Cowburn RF(2001). Localization of active forms of C-jun kinase (JNK) and p38 kinase in Alzheimer's disease brains at different stages of neurofibrillary degeneration. J Alzheimers Dis, 3:41-48
[79] Zhu X(2001). Activation of MKK6, an upstream activator of p38, in Alzheimer's disease. J Neurochem, 79:311-8
[80] Zhu X, Rottkamp CA, Boux H, Takeda A, Perry G, Smith MA(2000). Activation of p38 kinase links tau phosphorylation, oxidative stress, and cell cycle-related events in Alzheimer disease. J Neuropathol Exp Neurol, 59:880-8
[81] Hensley K(1999). p38 kinase is activated in the Alzheimer's disease brain. J Neurochem, 72:2053-8
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