Synergy of interleukin 10 and toll‐like receptor 9 signalling in B cell proliferation: Implications for lymphoma pathogenesis. Issue 5 (17th October 2016)

• Record Type: Journal Article
• Authors: Feist, Maren; Kemper, Judith; Taruttis, Franziska; Rehberg, Thorsten; Engelmann, Julia C.; Gronwald, Wolfram; Hummel, Michael; Spang, Rainer; Kube, Dieter
• Is Part Of: International journal of cancer. Volume 140:Issue 5(2017:Mar. 01)
• Page Start: 1147
• Page End: 1158
• Publication Date: 2016-10-17
• Subjects: toll‐like receptor -- interleukin -- cyclin‐dependent kinase -- B cell proliferation; Cancer -- Periodicals; Cancer -- Prevention -- Periodicals; 616.994
• DOI: 10.1002/ijc.30444
• Languages: English
• ISSNs: 0020-7136

Abstract

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, α‐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‐κB 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. Abstract : What's new? The proto‐oncogene c‐Myc ( MYC ) serves an influential role in B cell lymphoma, with unusually high MYC expression overcoming cell cycle arrest and driving B‐cell proliferation. Yet, not all cells require MYC for aberrant proliferation. Here, stimulation of MYC‐deprived B cells by factors derived from the germinal centre environment induced B cell proliferation, in the absence of mutations in participating pathways. In particular, stimulation by interleukin‐10 and the Toll‐like receptor agonist CpG resulted in simultaneous STAT3/NF‐κB activation. This joint STAT3/NF‐κB activity could substitute for aberrant MYC and possibly play an important role in lymphomagenesis as well as normal B cell development.