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Volume 3 Supplement 2

21st European Workshop for Rheumatology Research

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Spontaneous activation of JNK-1 and PI-3 kinase can be induced in lupus-like chronic GVHD in the P->F1 model

Abnormalities in intracellular signaling pathways have been described in human SLE however, it is not clear whether they are primary, predisposing events or secondary to SLE expression. To address this question, we used a murine model of SLE (chronic P->F1 GVHD) and compared the function of a broad range of intracellular signaling pathways. In this model, SLE-like disease is induced in normal F1 mice by injection of parental CD4+ T cells and is mediated predominantly by Th2 cytokines. In contrast, acute GVHD is a cell-mediated anti-host response induced by CD4 and CD8 donor T cells and both Th1 and Th2 cytokines. Spleen cell lysates from control and GVHD mice (day 10 and 21) were immunoprecipitated with antibodies to Raf-1, ERK-1, JNK-1, p38 MAPK and PI-3 kinase and the function of the precipitated kinases determined using a specific substrate for each kinase. Raf-1 and ERK1 were selectively increased in acute GVHD (2-fold) only, whereas JNK-1 and PI-3 kinases were increased in both acute and chronic GVHD. This increase was approximately two fold greater for acute vs. chronic GVHD mice for both kinases. p38 MAPK was not increased over control in either form of GVHD and may reflect the earlier peak of IL-2 (day 3) in this model. The data suggest that Raf-1 and ERK-1 may be important in CD8 driven cell mediated immune responses whereas JNK-1 and PI-3 kinase signaling may be important in CD4 driven antibody mediated immune response. Studies are under way using purified T cell subsets to confirm this hypothesis. However these data support the idea that the signaling abnormalities reported in human SLE may be secondary to a continuous immune activation rather than indicative of a primary predisposing event.

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Niculescu, F., Nguyen, P., Rus, V. et al. Spontaneous activation of JNK-1 and PI-3 kinase can be induced in lupus-like chronic GVHD in the P->F1 model. Arthritis Res Ther 3 (Suppl 2), P035 (2001).

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