Abstract
Wild type p53-induced phosphatase 1 (Wip1) is a phosphatase which belongs to protein phosphatase type 2C family, which have been predominantly linked to cell growth and to cellular stress signaling. Numerous downstream targets of Wip1 have been identified, and genetic studies confirm that some play a part in tumorigenesis. Recent evidence highlights a new role for Wip1 in the regulation of NF-κB p65, which indicated that it might play a critical role in immune system. However, its regulation role in central nervous system (CNS) remains poorly understood. To elaborate whether Wip1 was involved in CNS injury, we performed a neuroinflammatory model by lipopolysaccharide (LPS) lateral–ventral injection in adult rats. Wip1 expression was strongly upregulated in active astrocytes in inflamed brain cortex. In vitro studies indicated that the upregulation of Wip1 may be involved in the subsequent astrocytic activation following LPS exposure, and knockdown of Wip1 in primary astrocytes by siRNA showed that Wip1 inhibited the synthesis of TNF-α. Collectively, these results suggested that Wip1 may be important in host defense in CNS immune response, which might provide a potent therapeutic target of neuroinflammation.
Similar content being viewed by others
References
Aronica E, Ravizza T, Zurolo E, Vezzani A (2012) Astrocyte immune responses in epilepsy. Glia 60:1258–1268
Bulavin DV, Phillips C, Nannenga B, Timofeev O, Donehower LA, Anderson CW, Appella E, Fornace AJ Jr (2004) Inactivation of the Wip1 phosphatase inhibits mammary tumorigenesis through p38 MAPK-mediated activation of the p16(Ink4a)-p19(Arf) pathway. Nat Genet 36:343–350
Chew J, Biswas S, Shreeram S, Humaidi M, Wong et, Dhillion MK, Teo H, Hazra A, Fang CC, Lopez-Collazo E, Bulavin DV, Tergaonkar V (2009) WIP1 phosphatase is a negative regulator of NF-kappaB signaling. Nat Cell Biol 11:659–666
Cui M, Huang Y, Tian C, Zhao Y, Zheng J (2011) FOXO3a inhibits TNF-alpha- and IL-1beta-induced astrocyte proliferation: Implication for reactive astrogliosis. Glia 59:641–654
di Penta A, Moreno B, Reix S, Fernandez-Diez B, Villanueva M, Errea O, Escala N, Vandenbroeck K, Comella JX, Villoslada P (2013) Oxidative stress and proinflammatory cytokines contribute to demyelination and axonal damage in a cerebellar culture model of neuroinflammation. PLoS One 8:e54722
Fiscella M, Zhang H, Fan S, Sakaguchi K, Shen S, Mercer WE, Vande Woude GF, O’Connor PM, Appella E (1997) Wip1, a novel human protein phosphatase that is induced in response to ionizing radiation in a p53-dependent manner. Proc Natl Acad Sci U S A 94:6048–6053
Glezer I, Simard AR, Rivest S (2007) Neuroprotective role of the innate immune system by microglia. Neuroscience 147:867–883
Gorina R, Font-Nieves M, Marquez-Kisinousky L, Santalucia T, Planas AM (2011) Astrocyte TLR4 activation induces a proinflammatory environment through the interplay between MyD88-dependent NFkappaB signaling, MAPK, and Jak1/Stat1 pathways. Glia 59:242–255
Guerra MC, Tortorelli LS, Galland F, Da Re C, Negri E, Engelke DS, Rodrigues L, Leite MC, Goncalves CA (2011) Lipopolysaccharide modulates astrocytic S100B secretion: a study in cerebrospinal fluid and astrocyte cultures from rats. J Neuroinflammation 8:128
Harrison M, Li J, Degenhardt Y, Hoey T, Powers S (2004) Wip1-deficient mice are resistant to common cancer genes. Trends Mol Med 10:359–361
Hirsch EC, Hunot S (2009) Neuroinflammation in Parkinson’s disease: a target for neuroprotection? Lancet Neurol 8:382–397
Hu X, Li P, Guo Y, Wang H, Leak RK, Chen S, Gao Y, Chen J (2012) Microglia/macrophage polarization dynamics reveal novel mechanism of injury expansion after focal cerebral ischemia. Stroke 43:3063–3070
Ifuku M, Katafuchi T, Mawatari S, Noda M, Miake K, Sugiyama M, Fujino T (2012) Anti-inflammatory/anti-amyloidogenic effects of plasmalogens in lipopolysaccharide-induced neuroinflammation in adult mice. J Neuroinflammation 9:197
Lowe J, Cha H, Lee MO, Mazur SJ, Appella E, Fornace AJ Jr (2012) Regulation of the Wip1 phosphatase and its effects on the stress response. Front Biosci 17:1480–1498
Lowe JM, Cha H, Yang Q, Fornace AJ Jr (2010) Nuclear factor-kappaB (NF-kappaB) is a novel positive transcriptional regulator of the oncogenic Wip1 phosphatase. J Biol Chem 285:5249–5257
Lu X, Ma O, Nguyen TA, Jones SN, Oren M, Donehower LA (2007) The Wip1 phosphatase acts as a gatekeeper in the p53-Mdm2 autoregulatory loop. Cancer Cell 12:342–354
Lu X, Nguyen TA, Moon SH, Darlington Y, Sommer M, Donehower LA (2008) The type 2C phosphatase Wip1: an oncogenic regulator of tumor suppressor and DNA damage response pathways. Cancer Metastasis Rev 27:123–135
Martino G (2004) How the brain repairs itself: new therapeutic strategies in inflammatory and degenerative CNS disorders. Lancet Neurol 3:372–378
Nguyen MD, Julien JP, Rivest S (2002) Innate immunity: the missing link in neuroprotection and neurodegeneration? Nat Rev Neurosci 3:216–227
Renton KW, Dibb S, Levatte TL (1999) Lipopolysaccharide evokes the modulation of brain cytochrome P4501A in the rat. Brain Res 842:139–147
Saijo K, Winner B, Carson CT, Collier JG, Boyer L, Rosenfeld MG, Gage FH, Glass CK (2009) A Nurr1/CoREST pathway in microglia and astrocytes protects dopaminergic neurons from inflammation-induced death. Cell 137:47–59
Salminen A, Kaarniranta K (2011) Control of p53 and NF-kappaB signaling by WIP1 and MIF: role in cellular senescence and organismal aging. Cell Signal 23:747–752
Satoh N, Maniwa Y, Bermudez VP, Nishimura K, Nishio W, Yoshimura M, Okita Y, Ohbayashi C, Hurwitz J, Hayashi Y (2011) Oncogenic phosphatase Wip1 is a novel prognostic marker for lung adenocarcinoma patient survival. Cancer Sci 102:1101–1106
Shreeram S, Demidov ON, Hee WK, Yamaguchi H, Onishi N, Kek C, Timofeev ON, Dudgeon C, Fornace AJ, Anderson CW, Minami Y, Appella E, Bulavin DV (2006) Wip1 phosphatase modulates ATM-dependent signaling pathways. Mol Cell 23:757–764
Sofroniew MV (2009) Molecular dissection of reactive astrogliosis and glial scar formation. Trends Neurosci 32:638–647
Sofroniew MV, Vinters HV (2010) Astrocytes: biology and pathology. Acta Neuropathol 119:7–35
Takekawa M, Adachi M, Nakahata A, Nakayama I, Itoh F, Tsukuda H, Taya Y, Imai K (2000) p53-inducible wip1 phosphatase mediates a negative feedback regulation of p38 MAPK-p53 signaling in response to UV radiation. EMBO J 19:6517–6526
Taylor JM, Main BS, Crack PJ (2013) Neuroinflammation and oxidative stress: co-conspirators in the pathology of Parkinson’s disease. Neurochem Int 62:803–819
Wang P, Rao J, Yang H, Zhao H, Yang L (2011) Wip1 overexpression correlated with TP53/p14(ARF) pathway disruption in human astrocytomas. J Surg Oncol 104:679–684
Yoda A, Toyoshima K, Watanabe Y, Onishi N, Hazaka Y, Tsukuda Y, Tsukada J, Kondo T, Tanaka Y, Minami Y (2008) Arsenic trioxide augments Chk2/p53-mediated apoptosis by inhibiting oncogenic Wip1 phosphatase. J Biol Chem 283:18969–18979
Author information
Authors and Affiliations
Corresponding authors
Additional information
Xiang Tan and Jingjing Zhang contributed equally to this work.
Rights and permissions
About this article
Cite this article
Tan, X., Zhang, J., Jin, W. et al. Wip1 Phosphatase Involved in Lipopolysaccharide-Induced Neuroinflammation. J Mol Neurosci 51, 959–966 (2013). https://doi.org/10.1007/s12031-013-0080-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12031-013-0080-y