Feist, Maren and Kemper, Judith and Taruttis, Franziska and Rehberg, Thorsten and Engelmann, Julia C. and Gronwald, Wolfram and Hummel, Michael and Spang, Rainer and Kube, Dieter (2017) Synergy of interleukin 10 and toll-like receptor 9 signalling in B cell proliferation: Implications for lymphoma pathogenesis. INTERNATIONAL JOURNAL OF CANCER, 140 (5). pp. 1147-1158. ISSN 0020-7136, 1097-0215
Full text not available from this repository. (Request a copy)Abstract
A network of autocrine and paracrine signals defines B cell homeostasis and is thought to be involved in transformation processes. Investigating interactions of these microenvironmental factors and their relation to proto-oncogenes as c-Myc (MYC) is fundamental to understand the biology of B cell lymphoma. Therefore, B cells with conditional MYC expression were stimulated with CD40L, insulin-like growth factor 1, alpha-IgM, Interleukin-10 (IL10) and CpG alone or in combination. The impact of forty different interventions on cell proliferation was investigated in MYC deprived cells and calculated by linear regression. Combination of CpG and IL10 led to a strong synergistic activation of cell proliferation (S-phase/doubling of total cell number) comparable to cells with high MYC expression. A synergistic up-regulation of CDK4, CDK6 and CCND3 expression by IL10 and CpG treatment was causal for this proliferative effect as shown by qRT-PCR analysis and inhibition of the CDK4/6 complex by PD0332991. Furthermore, treatment of stimulated MYC deprived cells with MLN120b, ACHP, Pyridone 6 or Ruxolitinib showed that IL10/CpG induced proliferation and CDK4 expression were JAK/STAT3 and IKK/NF-jB dependent. This was further supported by STAT3 and p65/RELA knockdown experiments, showing strongest effects on cell proliferation and CDK4 expression after double knockdown. Additionally, chromatin immunoprecipitation revealed a dual binding of STAT3 and p65 to the proximal promotor of CDK4 after IL10/CpG treatment. Therefore, the observed synergism of IL10R and TLR9 signalling was able to induce proliferation in a comparable way as aberrant MYC and might play a role in B cell homeostasis or transformation.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | NF-KAPPA-B; C-MYC; GENE-EXPRESSION; STAT3; ACTIVATION; SURVIVAL; LYMPHOCYTES; GROWTH; CYCLE; IDENTIFICATION; toll-like receptor; interleukin; cyclin-dependent kinase; B cell proliferation |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Institut für Funktionelle Genomik > Lehrstuhl für Funktionelle Genomik (Prof. Oefner) Medicine > Institut für Funktionelle Genomik > Lehrstuhl für Statistische Bioinformatik (Prof. Spang) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 14 Dec 2018 13:01 |
| Last Modified: | 12 Feb 2019 08:29 |
| URI: | https://pred.uni-regensburg.de/id/eprint/351 |
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