Format

Send to

Choose Destination
J Biol Chem. 2015 Mar 6;290(10):6574-83. doi: 10.1074/jbc.M114.617886. Epub 2015 Jan 16.

Inflammation and pyroptosis mediate muscle expansion in an interleukin-1β (IL-1β)-dependent manner.

Author information

1
From the Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California 90048.
2
From the Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California 90048, Greater Los Angeles Veterans Administration, Los Angeles, California, and.
3
From the Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California 90048, bhowmickn@cshs.org.
4
Department of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, California.
5
From the Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California 90048, Greater Los Angeles Veterans Administration, Los Angeles, California, and bhowmickn@cshs.org.

Abstract

Muscle inflammation is often associated with its expansion. Bladder smooth muscle inflammation-induced cell death is accompanied by hyperplasia and hypertrophy as the primary cause for poor bladder function. In mice, DNA damage initiated by chemotherapeutic drug cyclophosphamide activated caspase 1 through the formation of the NLRP3 complex resulting in detrusor hyperplasia. A cyclophosphamide metabolite, acrolein, caused global DNA methylation and accumulation of DNA damage in a mouse model of bladder inflammation and in cultured bladder muscle cells. In correlation, global DNA methylation and NLRP3 expression was up-regulated in human chronic bladder inflammatory tissues. The epigenetic silencing of DNA damage repair gene, Ogg1, could be reversed by the use of demethylating agents. In mice, demethylating agents reversed cyclophosphamide-induced bladder inflammation and detrusor expansion. The transgenic knock-out of Ogg1 in as few as 10% of the detrusor cells tripled the proliferation of the remaining wild type counterparts in an in vitro co-culture titration experiment. Antagonizing IL-1β with Anakinra, a rheumatoid arthritis therapeutic, prevented detrusor proliferation in conditioned media experiments as well as in a mouse model of bladder inflammation. Radiation treatment validated the role of DNA damage in the NLRP3-associated caspase 1-mediated IL-1β secretory phenotype. A protein array analysis identified IGF1 to be downstream of IL-1β signaling. IL-1β-induced detrusor proliferation and hypertrophy could be reversed with the use of Anakinra as well as an IGF1 neutralizing antibody. IL-1β antagonists in current clinical practice can exploit the revealed mechanism for DNA damage-mediated muscular expansion.

KEYWORDS:

8-Oxoguanine Glycosylase (OGG1); Bladder Inflammation; Caspase 1 (CASP1); Cell Death; DNA Damage; Fibroblast; Hyperplasia; Hypertrophy; Insulin-like Growth Factor (IGF); Pyroptosis

PMID:
25596528
PMCID:
PMC4358290
DOI:
10.1074/jbc.M114.617886
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center