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Datasets  >  signalling dataset  >  Role of certain MAP kinases...

Role of certain MAP kinases in the regulation of IL-10 and IL-12, IFN-gamma production

signalling dataset

We have microarray data on macrophages and DC from different genetic backgrounds of mice, stimulated with CpG, in the presence or absence of a MEK inhibitor, and further data on the role of certain MAP kinases in the regulation of IL-10 and IL-12, IFN-gamma production.

Using pharmacological inhibitors, or macrophages and DC from mice carrying a null mutation in MAP kinase signalling molecule(s), we have evidence for a role of certain MAP kinases in the regulation of IL-10 and IL-12, IFN-gamma production. The work on the role of the MAP kinases, TPL-2 and ERK in upregulation of IL-10 production and negative regulation of IL-12 and IFN-gamma induction, has been under review with the Journal of Experimental Medicine and is now about to be resubmitted – this has taken longer than expected due to breeding problems with mice and the requirement to make new retroviral transcription factor constructs as requested by the reviewers (Kaiser, Cooke, Rajsbaum, Wu, Papoutsopoulou, Ley,and O’Garra).

This work forms the basis of the microarray analysis of macrophages and DC from different genetic backgrounds of mice, stimulated with CpG, in the presence or absence of a MEK inhibitor, to identify downstream transcription factors responsible for the regulation of IL-10, IL-12 and IFN-gamma in collaboration with P. Ricciardi Castagnoli. Additional findings on the dominant role of the MAP kinase p38 in TLR ligand induced production of IL-10 were published (Kaiser. Wu, O’Garra et al; and one collaborative paper has been published (Papoutsopoulou et al., 2006).

Furthermore, R. Rajsbaum has published a manuscript in the European Journal of Immunology, titled “Type-1 Interferon-dependent and independent expression of tripartite motif proteins in immune cells” by Ricardo Rajsbaum, Jonathan P. Stoye and Anne O’Garra. In this paper he has revealed that TRIM molecules can be grouped in clusters based on their patterns of mRNA expression in the different cell populations. His main work shows that a group of TRIMs that share similar structural features, namely the COS-FN3 domains important in protein-protein interactions and localization to the microtubules, are preferentially expressed in the CD4+ T cell subsets, suggesting they may share a common function in these cells. On the other hand, a different cluster of TRIMs is constitutively expressed at high levels in plasmacytoid dendritic cells (pDC). Conversely, he found that a different group containing a large number of TRIM genes are induced in primary mouse macrophages, myeloid DC (mDC) and pDC upon influenza virus infection in a type-1 IFN dependent manner, suggesting an anti-viral function. However, stimulation of macrophages and mDC with LPS and double stranded RNA also led to type-1 IFN dependent up-regulation of these TRIM genes, demonstrating that their expression is not directly regulated by the virus, and that they may have broader functions in innate immune responses. A subgroup of the TRIMs induced in macrophages and DC by viruses in a type-I IFN dependent manner, mapped to mouse chromosome 7, which is syntenic to human chromosome 11, where TRIMs with known anti-viral activity are localised, suggesting that they may have co-evolved to combat viruses. The study highlights the importance of TRIM molecules as effectors of the innate immune response.

The analysis of this data resulted from R. Rajsbaum training on the Mugen Course run by Castagnoli, and forms the basis of analysis of the data obtained in the microarray study listed below which is a collaboration with Prof. Ricciardi-Castagnoli, which he and Xuemei Wu have been analysing in the last months.

RNA was sent to Partner P. Ricciardi Castagnoli (UNIMIB) for microarray analysis of macrophages and DC from different genetic backgrounds of mice, stimulated with CpG, in the presence or absence of a MEK inhibitor, to identify downstream transcription factors responsible for the regulation of IL-10, IL-12 and IFN-??. (experiments performed by X. Wu & R.Rajsbaum are accomplished as part of those experiments). We have received the data and Ricardo Rajsbaum and Xuemei Wu are currently analysing.
My group is (Ricardo Rajsbaum and Xuemei Wu) is involved in the pathway analysis database initiative. Regarding the knowledge portal, the microarray data on our experiment will be submitted in the coming year and a manuscript will be submitted for publication in collaboration with Prof. Ricciardi Castagnoli. Information on protocols to generate DCs etc have been submitted by the student, Ricardo Rajsbaum and will be placed on the portal.




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