Phospholipase C activity was measured using p-nitrophenyl phosphorylcholine as described before by Kurioka and Matsuda

n of NK cells failed to alter the appearance of cerebral symptoms or the outcome of CM in P. berghei infected mice, while another study found that IFN-g secretion by NK cells was important for recruitment of CXCR3+ CD4+ and CD8+ T cells to the brain and development of cerebral disease. On the other hand, cell depletion and cell transfer experiments in vivo have shown that IFN-g production by CD4+ and CD8+ T cells can both contribute to CM pathogenesis. Results from our adoptive transfer studies in Jak3W81R homozygotes provide additional insight into this question. We observed that: a) total spleen cells from C57BL/10J mice were the only cell population that could fully restore CM-susceptibility in the mutants; b) total T cells and purified CD8+ T cells had a similar effect and caused partial but significant reversion to CM susceptibility in Jak3W81R animals; c) transfer of purified wild type NK cells had no impact on the CM resistance of the Jak3W81R mutants. These results strongly suggest that CD8+ T cells are the major cell type contributing to CM pathogenesis, although other spleen cell populations or other cell:cell interactions, for example T cell dependent NK cell Darapladib web activation, appear to be required to observe the full effect. Nevertheless, our results clearly establish a role of the Jak3 kinase in the pathogenesis of cerebral malaria. This participation may reflect the function of Jak3 in the ontogeny of cell populations that produce IFN-g and other soluble mediators of the pathological inflammatory response that are absent in the Jak3W81R mutant. The protective effect of Jak3W81R may additionally involve inhibition of gc chaindependent cytokine receptor signaling in other cell types, whose ontogeny is not affected by the Jak3 mutation. Nevertheless, our results suggest that pharmacological inhibition of Jak3 may be of therapeutic value in CM. Several small molecule Jak3 inhibitors have been developed and are undergoing clinical evaluation for inflammatory conditions such as rheumatoid PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/22184166 arthritis, psoriasis and several autoimmune conditions including autoimmune encephalitis, and rejection of organ transplants. Our findings raise the interesting possibility that Jak3 inhibition by some of these molecules may represent a novel strategy for intervention in clinical cases of CM, a proposition that can be tested experimentally. An intriguing finding of our study is the intermediate CMresistance phenotype characteristic of Jak3W81R/+ heterozygotes, with a proportion of these animals either succumbing late in the cerebral phase or completely surviving the cerebral phase. This was first noticed in haplotype analyses of G3 mice of pedigree 48, with animals heterozygote for the chromosome 8 markers being found in both the CM-resistant and CM-susceptible groups, and subsequently verified during P. berghei infection of genotyped Jak3W81R/+ hetrozygotes. The effect is not caused by the genetic background of the animals and is specific for Jak3W81R/+ heterozygosity, as is seen when the mutation is introduced onto either B6/B10 or B6/B10-129S1 mixed genetic backgrounds. The cellular and molecular basis of co-dominance of the Jak3W81R mutation is intriguing. It could be explained either by a partial loss of Jak3 function in a dosage dependent pathway or by a specific dominant negative effect of the Jak3W81R allele. The observation that mice heterozygote for a null Jak3 mutation are as susceptible to CM as wild type B6 controls clearly argues for th

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