title: MK2 and Fas receptor contribute to the severity of CNS demyelination.
abstract: Models of inflammatory or degenerative diseases demonstrated that the protein-kinase MK2 is a key player in inflammation. In this study we examined the role of MK2 in MOG35-55-induced experimental autoimmune encephalomyelitis (EAE), the animal model for multiple sclerosis. In MK2-deficient (MK2-/-) mice we found a delayed onset of the disease and MK2-/- mice did not recover until day 24 after EAE induction. At this day a higher number of leukocytes in the CNS of MK2-/- mice was found. TNFα was not detectable in serum of MK2-/- mice in any stage of EAE, while high TNFα levels were found at day 16 in wild-type mice. Further investigation revealed an increased expression of FasR mRNA in leukocytes isolated from CNS of wild-type mice but not in MK2-/- mice, however in vitro stimulation of MK2-/- splenocytes with rmTNFα induced the expression of FasR. In addition, immunocomplexes between the apoptosis inhibitor cFlip and the FasR adapter molecule FADD were only detected in splenocytes of MK2-/- mice at day 24 after EAE induction. Moreover, the investigation of blood samples from relapsing-remitting multiple sclerosis patients revealed reduced FasR mRNA expression compared to healthy controls. Taken together, our data suggest that MK2 is a key regulatory inflammatory cytokines in EAE and multiple sclerosis. MK2-/- mice showed a lack of TNFα and thus might not undergo TNFα-induced up-regulation of FasR. This may prevent autoreactive leukocytes from apoptosis and may led to prolonged disease activity. The findings indicate a key role of MK2 and FasR in the regulation and limitation of the immune response in the CNS.
authors: Department of Neurology, Justus-Liebig-University Giessen, Giessen, Germany; Theodor-Kocher-Institute, Universtiy of Bern, Bern, Switzerland.
authors: Silvia M
authors: SM
authors: Tietz
authors: Department of Child Neurology, Justus-Liebig-University Giessen, Giessen, Germany.
authors: Regina
authors: R
authors: Hofmann
authors: Department of Neurology, Justus-Liebig-University Giessen, Giessen, Germany.
authors: Tobias
authors: T
authors: Thomas
authors: Department of Neurology, Clinical Neuroimmunology Group, Philipps-University, Marburg, Germany.
authors: Björn
authors: B
authors: Tackenberg
authors: Institute of Biochemistry, Hannover Medical School, Hannover, Germany.
authors: Matthias
authors: M
authors: Gaestel
authors: Department of Neurology, Justus-Liebig-University Giessen, Giessen, Germany.
authors: Martin
authors: M
authors: Berghoff
mesh_terms: D000328:Adult; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002452:Cell Count; D002490:Central Nervous System / Q000276:immunology / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000097:blood / Q000276:immunology / Q000378:metabolism*; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency / Q000378:metabolism*; D007962:Leukocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D009103:Multiple Sclerosis / Q000097:blood / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012008:Recurrence; D013154:Spleen / Q000166:cytology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects; D019014:fas Receptor / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D000099190:MAP-Kinase-Activated Kinase 2
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D017346:Protein Serine-Threonine Kinases; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D000099190:MAP-Kinase-Activated Kinase 2