Telomere-mediated chromosomal instability triggers TLR4 induced inflammation and death in mice.
BACKGROUND
Telomeres are essential to maintain chromosomal stability. Cells derived from mice lacking telomerase RNA component (mTERC-/- mice) display elevated telomere-mediated chromosome instability. Age-dependent telomere shortening and associated chromosome instability reduce the capacity to respond to cellular stress occurring during inflammation and cancer. Inflammation is one of the important risk factors in cancer progression. Controlled innate immune responses mediated by Toll-like receptors (TLR) are required for host defense against infection. Our aim was to understand the role of chromosome/genome instability in the initiation and maintenance of inflammation.


RESULTS
We examined the function of TLR4 in telomerase deficient mTERC-/- mice harbouring chromosome instability which did not develop any overt immunological disorder in pathogen-free condition or any form of cancers at this stage. Chromosome instability was measured in metaphase spreads prepared from wildtype (mTERC+/+), mTERC+/- and mTERC-/- mouse splenocytes. Peritoneal and/or bone marrow-derived macrophages were used to examine the responses of TLR4 by their ability to produce inflammatory mediators TNFalpha and IL6. Our results demonstrate that TLR4 is highly up-regulated in the immune cells derived from telomerase-null (mTERC-/-) mice and lipopolysaccharide, a natural ligand for TLR4 stabilises NF-kappaB binding to its promoter by down-regulating ATF-3 in mTERC-/- macrophages.


CONCLUSIONS
Our findings implied that background chromosome instability in the cellular level stabilises the action of TLR4-induced NF-kappaB action and sensitises cells to produce excess pro-inflammatory mediators. Chromosome/genomic instability data raises optimism for controlling inflammation by non-toxic TLR antagonists among high-risk groups.
Bhattacharjee
Rabindra N
RN
Akira Innate Immunity Project, Exploratory Research for Advanced Technology (ERATO), Osaka University, Osaka, Japan. rbhatta4@uwo.ca
Banerjee
Birendranath
B
Akira
Shizuo
S
Hande
M Prakash
MP
D000818:Animals; D015153:Blotting, Western; D043171:Chromosomal Instability / Q000235:genetics / Q000502:physiology*; D024202:Electrophoretic Mobility Shift Assay; D017403:In Situ Hybridization; D007249:Inflammation / Q000235:genetics / Q000378:metabolism* / Q000401:mortality; D015850:Interleukin-6 / Q000378:metabolism; D051379:Mice; D012313:RNA; D019098:Telomerase; D016615:Telomere / Q000235:genetics / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D015850:Interleukin-6; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; C422952:telomerase RNA; D012313:RNA; D019098:Telomerase