+ Site Statistics
References:
54,258,434
Abstracts:
29,560,870
PMIDs:
28,072,757
+ Search Articles
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ PDF Full Text
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Translate
+ Recently Requested

Physiological levels of TNFalpha stimulation induce stochastic dynamics of NF-kappaB responses in single living cells



Physiological levels of TNFalpha stimulation induce stochastic dynamics of NF-kappaB responses in single living cells



Journal of Cell Science 123(Pt 16): 2834-2843



Nuclear factor kappa B (NF-kappaB) signalling is activated by cellular stress and inflammation and regulates cytokine expression. We applied single-cell imaging to investigate dynamic responses to different doses of tumour necrosis factor alpha (TNFalpha). Lower doses activated fewer cells and those responding showed an increasingly variable delay in the initial NF-kappaB nuclear translocation and associated IkappaBalpha degradation. Robust 100 minute nuclear:cytoplasmic NF-kappaB oscillations were observed over a wide range of TNFalpha concentrations. The result is supported by computational analyses, which identified a limit cycle in the system with a stable 100 minute period over a range of stimuli, and indicated no co-operativity in the pathway activation. These results suggest that a stochastic threshold controls functional all-or-nothing responses in individual cells. Deterministic and stochastic models simulated the experimentally observed activation threshold and gave rise to new predictions about the structure of the system and open the way for better mechanistic understanding of physiological TNFalpha activation of inflammatory responses in cells and tissues.

(PDF emailed within 0-6 h: $19.90)

Accession: 055001980

Download citation: RISBibTeXText

PMID: 20663918

DOI: 10.1242/jcs.069641


Related references

Single TNFalpha trimers mediating NF-kappaB activation: stochastic robustness of NF-kappaB signaling. Bmc Bioinformatics 8(): 376-376, 2007

The stimulation of arginine transport by TNFalpha in human endothelial cells depends on NF-kappaB activation. Biochimica et Biophysica Acta 1664(1): 45-52, 2004

Stimulation of the human cytomegalovirus IE enhancer/promoter in HL-60 cells by TNFalpha is mediated via induction of NF-kappaB. Virology 208(1): 197-206, 1995

Regulation of CDK4 expression levels by TGFbeta, TNFalpha, IL-1, NF-kappaB and Ras determines cellular proliferative responses to these regulators of epidermal growth. Journal of Investigative Dermatology 119(1): 279, July, 2002

Measuring dynamics of caspase-8 activation in a single living HeLa cell during TNFalpha-induced apoptosis. Biochemical and Biophysical Research Communications 304(2): 217-222, 2003

NF-kappaB activation prevents apoptotic oxidative stress via an increase of both thioredoxin and MnSOD levels in TNFalpha-treated Ewing sarcoma cells. Febs Letters 578(1-2): 111-115, 2004

NF-kappaB activation results in rapid inactivation of JNK in TNFalpha-treated Ewing sarcoma cells: A mechanism for the anti-apoptotic effect of NF-kappaB. Oncogene 20(32): 4365-4372, 19 July, 2001

Bovine TLR2 and TLR4 properly transduce signals from Staphylococcus aureus and E. coli, but S. aureus fails to both activate NF-kappaB in mammary epithelial cells and to quickly induce TNFalpha and interleukin-8 (CXCL8) expression in the udder. Molecular Immunology 45(5): 1385-1397, 2007

Morphological responses of single endothelial cells exposed to physiological levels of fluid shear stress. Frontiers of Medical and Biological Engineering 5(2): 79-87, 1993

Silibinin inhibits constitutive and TNFalpha-induced activation of NF-kappaB and sensitizes human prostate carcinoma DU145 cells to TNFalpha-induced apoptosis. Oncogene 21(11): 1759-1767, 2002

Specific inhibition of NF-kappaB allows TNFalpha to selectively overcome the protective effect of survival factors and induce mesangial cell apoptosis. Journal of the American Society of Nephrology 10(PROGRAM AND ABSTR ISSUE): 501A, Sept, 1999

Single-molecule imaging of stochastic signaling events in living cells. Cold Spring Harbor Protocols 2012(3): 267-278, 2012

IkappaB kinase B , but not NF-kappaB-inducing kinase or IKKalpha, represents a therapeutic target for modulation of Fas, IL-1beta and TNFalpha-mediated NF-kappaB activation in intestinal epithelial cells. Gastroenterology 118(4 Suppl 2 Part 1): AGA A587, April, 2000

Multi-parameter analysis of the kinetics of NF-kappaB signalling and transcription in single living cells. Journal of Cell Science 115(Pt 6): 1137-1148, 2002