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.
Highlights
The p38 mitogen-activated protein kinase (MAPK) pathway mediates cellular responses to injurious stress and immune signalling serving cell type-specific inflammatory functions that can result in cytokine and chemokine production
We found a delayed onset of EAE around day 13 in MK22/2 mice compared to wild-type controls which developed clinical symptoms around day 12 post immunization (p = 0.0433) (Table 2)
The Fas-receptor mRNA in patients with RRMS is decreased and correlates negatively with disabilities After we found the decreased mRNA expression of FasR in leukocytes isolated from the central nervous system (CNS) of MK22/2 mice we studied whether patients with RR-multiple sclerosis (MS) show altered FasR mRNA levels in different stages of the disease
Summary
The p38 mitogen-activated protein kinase (MAPK) pathway mediates cellular responses to injurious stress and immune signalling serving cell type-specific inflammatory functions that can result in cytokine and chemokine production. Amongst the substrates of the p38 MAPK/MK2 pathway there are mRNA-AU-rich-element (ARE-)-binding proteins which regulate mRNA stability and translation of key inflammatory cytokines such as TNFa, IFNc, IL-6 and IL-1b [1,2]. Against this background MK2 is an interesting target in inflammation and has been studied in various disease models. After spinal cord injury reduced loss of neuronal cells and myelin was observed in MK2 knockout mutants [6]. These findings suggest that a lack of MK2 reduces inflammation and protects against destruction of brain cells and cells of other tissues
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