| Summary: | Antigen presenting cells such as macrophages and dendritic cells play an important role between the interface of the innate and adaptive immune responses. One property shared by dendritic cells and macrophages is that upon activation they secrete either pro- or anti-inflammatory cytokines dependent on the pathogen derived product and the T cell derived signal they encounter. The panel of cytokines they produce determines the class of the adaptive immune response. Tpl-2 was originally described as a proto-oncogene. It was later found to function as a Map-3 kinase leading to phosphorylation of MEK and ERK. Upon stimulation of dendritic cells and macrophages with Toll like receptor ligands (TLR) such as LPS and CpG, Tpl-2 phosphorylates MEK, which in turn phosphorylates ERK, leading to production of cytokines. In the Tpl-2 knockout mice, it has been shown that TNF production is decreased. We have confirmed this finding and shown that this is both at the transcriptional and post-transcription level. In the complete absence of Tpl-2 we have shown that production of the suppressive cytokine IL-10 is reduced in response to TLR stimulation in macrophages and dendritic cells. On the other hand, when macrophages and dendritic cells are stimulated with LPS or CpG in the absence of Tpl-2, production of IL-12 is increased. IFN-b is also upregulated in absence of Tpl-2. Tpl-2 can regulate IL-12 either directly via IL-10, but also independently of IL-10 via ERK. IL-10 is an important cytokine in regulating the immune response in order to inhibit immune pathology. We crossed the Tpl-2 knockout with an IL-10 knockout mouse in order to investigate whether Tpl-2 regulates IL-12 and IFN-b in the complete absence of IL-10. These studies are currently in progress. Preliminary results however, show that the Tpl-2/IL-10 double knockout develop diarrhoea and colitis around 8 weeks of age, leading to minimal weight gain and even weight loss compared to littermates. This is in contrast to the Tpl-2 knockout, which does not develop colitis and the IL-10 knockout, which only develops colitis at 4 months of age. These findings have important implications for treatment of autoimmune diseases with drugs that inhibit ERK, to inhibit TNF mediated pathology. The aim of this thesis was to investigate to role ERK has in regulating cytokine production in DC and macrophages. We used two different strategies to do this. Firstly we pharmacologically blocked ERK phosphorylation with an inhibitor. Secondly we used genetically modified mice lacking Tpl-2.
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