involvement of IL21 activated genes on cytokine signalling could also e plain its relation to I��B kinase NF ��B cascade and NF ��B import into nu cleus, gene sets characteristic for Toll like receptor path ways, Jak STAT and chemokine signalling pathway, but also pathways in cancer are enriched. IL21 suppressed genes are characteristic for nucleotidyltransferase activity, cytoskeletal protein or phospholipid binding thus affecting cell shape, morphogenesis or chemota is. BAFF activated genes are involved in metabolic processes of amino acids and chromatin remodelling, whereas downregulated genes are part of lipoprotein metabolic process, protein amino acid acylation.
The CD40L mediated gene e pression changes positively affect MHC class I receptor activity and thus antigen pro cessing and presentation of peptide antigen, the regulation of membrane potential, small GTPase mediated signal transduction as well as metabolic processes. In contrast, CD40L suppressed genes are involved in phospholipase ac tivity or negative regulation of Carfilzomib transcription. Gene e pression changes in transformed germinal centre B cells of selected microarray results and validation by quantitative real time PCR Stimulation of BL2 cells led to changes in the e pres sion of genes involved in cell cell communications, in cluding changes in HLA, PECAM, CD1, CD86 or members of the signalling lymphocyte activation mol ecule family. Interestingly, e pression of the HLA group of genes was positively regulated as a re sult of all stimulations. IL21 affects, for e ample HLA B, C and E e pression.
The greatest upregula tion was observed for HLA DPA1, DQA1 and DQB1 following BAFF, CD40L and IgM treatment. Further more, CIITA was activated by CD40L and IgM. E pres sion of the ICAM1 gene, which encodes a protein involved in cellular adhesion and costimulatory signalling and leukocyte trans endothelial migration, is activated by all the stimuli used. IL21 treatment has the highest impact on ICAM1 activa tion. CD58, a ligand of CD2, is activated by CD40L and IgM treatment. SLAMF associated proteins are important immuno modulatory receptors with roles in cytoto icity, humoral immunity, autoimmunity, cell survival, lymphocyte de velopment, and cell adhesion. Whereas SLAMF1, 3 and 7 are strongly upregulated by BCR crosslinking, SLAMF6 is inhibited. This inhibition is most prominent in response to IgM.
In contrast, CD40L treatment is associated with a decreased SLAMF3 e pression. Defined elements of the chemokine system are specif ically affected IL21 upregulates CCR7, C CR5 and C CL10, CD40L modulates the e pression of CCL5, CCL17, C CR7 and C CL10, whereas IgM treatment affects CCR7, C CR7 and C CL10. The chemokine receptor CCR7, involved in germinal centre B cell homing is affected by CD40L but much stronger through IgM. CCR7 plays a pivotal role in homing of tumour cells into lymphoma supporting niches in secondary lymphoid organs. The chemokine C CL10 is involved in chemota is for monocytes