title: p38 MAPK signaling acts upstream of LIF-dependent neuroprotection during photoreceptor degeneration.
abstract: In many blinding diseases of the retina, loss of function and thus severe visual impairment results from apoptotic cell death of damaged photoreceptors. In an attempt to survive, injured photoreceptors generate survival signals to induce intercellular protective mechanisms that eventually may rescue photoreceptors from entering an apoptotic death pathway. One such endogenous survival pathway is controlled by leukemia inhibitory factor (LIF), which is produced by a subset of Muller glia cells in response to photoreceptor injury. In the absence of LIF, survival components are not activated and photoreceptor degeneration is accelerated. Although LIF is a crucial factor for photoreceptor survival, the detailed mechanism of its induction in the retina has not been elucidated. Here, we show that administration of tumor necrosis factor-alpha (TNF) was sufficient to fully upregulate Lif expression in Muller cells in vitro and the retina in vivo. Increased Lif expression depended on p38 mitogen-activated protein kinase (MAPK) since inhibition of its activity abolished Lif expression in vitro and in vivo. Inhibition of p38 MAPK activity reduced the Lif expression also in the model of light-induced retinal degeneration and resulted in increased cell death in the light-exposed retina. Thus, expression of Lif in the injured retina and activation of the endogenous survival pathway involve signaling through p38 MAPK.
authors.affiliation: Lab for Retinal Cell Biology, Department of Ophthalmology, University of Zurich, Zurich 8091, Switzerland.
authors.forename: C
authors.initials: C
authors.lastname: Agca
authors.forename: A
authors.initials: A
authors.lastname: Gubler
authors.forename: G
authors.initials: G
authors.lastname: Traber
authors.forename: C
authors.initials: C
authors.lastname: Beck
authors.forename: C
authors.initials: C
authors.lastname: Imsand
authors.forename: D
authors.initials: D
authors.lastname: Ail
authors.forename: C
authors.initials: C
authors.lastname: Caprara
authors.forename: C
authors.initials: C
authors.lastname: Grimm
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects / Q000528:radiation effects; D019610:Cytoprotection / Q000187:drug effects / Q000528:radiation effects; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects / Q000528:radiation effects; D004789:Enzyme Activation / Q000187:drug effects / Q000528:radiation effects; D063928:Ependymoglial Cells / Q000187:drug effects / Q000201:enzymology / Q000473:pathology / Q000528:radiation effects; D058449:Intravitreal Injections; D053605:Leukemia Inhibitory Factor / Q000235:genetics / Q000378:metabolism*; D008027:Light; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000528:radiation effects; D051379:Mice; D008810:Mice, Inbred C57BL; D020419:Photoreceptor Cells, Vertebrate / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology* / Q000528:radiation effects; D051381:Rats; D012162:Retinal Degeneration / Q000201:enzymology / Q000473:pathology*; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects / Q000528:radiation effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D053605:Leukemia Inhibitory Factor; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases