+ Site Statistics
+ Search Articles
+ PDF Full Text Service
How our service works
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ Translate
+ Recently Requested

Synergy between interferon-gamma and tumor necrosis factor-alpha in transcriptional activation is mediated by cooperation between signal transducer and activator of transcription 1 and nuclear factor kappaB



Synergy between interferon-gamma and tumor necrosis factor-alpha in transcriptional activation is mediated by cooperation between signal transducer and activator of transcription 1 and nuclear factor kappaB



Journal of Biological Chemistry 272(23): 14899-14907



Interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha) cooperate to induce the expression of many gene products during inflammation. The present report demonstrates that a portion of this cooperativity is mediated by synergism between two distinct transcription factors: signal transducer and activator of transcription 1 (STAT1) and nuclear factor kappa-B (NF-kappa-B). IFN-gamma and TNF-alpha synergistically induce expression of mRNAs encoding interferon regulatory factor-1 (IRF-1), intercellular adhesion molecule-1, Mig (monokine induced by gamma-interferon), and RANTES (regulated on activation normal T cell expressed and secreted) in normal but not STAT1-deficient mouse fibroblasts, indicating a requirement for STAT1. Transient transfection assays in fibroblasts using site-directed mutants of a 1.3-kilobase pair sequence of the IRF-1 gene promoter revealed that the synergy was dependent upon two sequence elements; a STAT binding element and a kappa-B motif. Artificial constructs containing a single copy of both a STAT binding element and a kappa-B motif linked to the herpes virus thymidine kinase promoter were able to mediate synergistic response to IFN-gamma and TNF-alpha; such response varied with both the relative spacing and the specific sequence of the regions between these two sites. Cooperatively responsive sequence constructs bound both STAT1-alpha and NF-kappa-B in nuclear extracts prepared from IFN-gamma- and/or TNF-alpha-stimulated fibroblasts, although binding of individual factors was not cooperative. Thus, the frequently observed synergy between IFN-gamma and TNF-alpha in promoting inflammatory response depends in part upon cooperation between STAT1-alpha and NF-kappa-B, which is most likely mediated by their independent interaction with one or more components of the basal transcription complex.

Please choose payment method:






(PDF emailed within 1 workday: $29.90)

Accession: 009502492

Download citation: RISBibTeXText

PMID: 9169460


Related references

Synergy between interferon-c and tumor necrosis factor-a in transcriptional activation is mediated by cooperation between signal transduction and activator of transcription 1 and nuclear factor kB. The Journal of Biological Chemistry 272: 899-907, 1997

Shiga toxin type 1 activates tumor necrosis factor-alpha gene transcription and nuclear translocation of the transcriptional activators nuclear factor-kappaB and activator protein-1. Blood 92(2): 558-566, 1998

Activation of nuclear factor-kappaB-dependent transcription by tumor necrosis factor-alpha is mediated through phosphorylation of RelA/-65 on serine 529. Journal of Biological Chemistry 273(45): 29411-29416, 1998

Interferon-gamma and tumor necrosis factor-alpha induce an immunoinhibitory molecule, B7-H1, via nuclear factor-kappaB activation in blasts in myelodysplastic syndromes. Blood 116(7): 1124-1131, 2010

Tumour necrosis factor-alpha and interferon-gamma synergistically activate the RANTES promoter through nuclear factor kappaB and interferon regulatory factor 1 (IRF-1) transcription factors. Biochemical Journal 350 Pt 1: 131-138, 2000

Tumor necrosis factor-alpha activation of nuclear transcription factor-kappaB in marrow macrophages is mediated by c-Src tyrosine phosphorylation of IkappaBUalpha. Journal of Biological Chemistry 273(45): 29417-29423, 1998

Role for nuclear factor-kappaB and signal transducer and activator of transcription 1/interferon regulatory factor-1 in cytokine-induced endothelin-1 release in human vascular smooth muscle cells. Molecular Pharmacology 64(4): 923-931, 2003

Cooperative activation of CCL5 expression by TLR3 and tumor necrosis factor-alpha or interferon-gamma through nuclear factor-kappaB or STAT-1 in airway epithelial cells. International Archives of Allergy and Immunology 152(Suppl. 1): 9-17, 2010

Involvement of double-stranded RNA-activated protein kinase in the synergistic activation of nuclear factor-kappaB by tumor necrosis factor-alpha and gamma-interferon in preneuronal cells. Journal of Biological Chemistry 274(8): 4801-4806, 1999

Pseudomonas aeruginosa slime glycolipoprotein is a potent stimulant of tumor necrosis factor alpha gene expression and activation of transcription activators nuclear factor kappaB and activator protein 1 in human monocytes. Infection and Immunity 71(8): 4614-4622, 2003

Tumor necrosis factor alpha induces gamma-glutamyltransferase expression via nuclear factor-kappaB in cooperation with Sp1. Biochemical Pharmacology 77(3): 397-411, 2009

Conjugated polyhydroxybenzene derivatives block tumor necrosis factor-alpha-mediated nuclear factor-kappaB activation and cyclooxygenase-2 gene transcription by targeting IkappaB kinase activity. Molecular Pharmacology 60(6): 1439-1448, 2001

Abnormal nuclear factor (NF)-kappaB signal pathway and aspirin inhibits tumor necrosis factor alpha-induced NF-kappaB activation in keloid fibroblasts. Dermatologic Surgery 33(6): 697-708, 2007

Role of NF-kappaB activity in apoptotic response of keratinocytes mediated by interferon-gamma, tumor necrosis factor-alpha, and tumor-necrosis-factor-related apoptosis-inducing ligand. Journal of Investigative Dermatology 117(4): 898-907, 2001

Antioxidant alpha-lipoic acid inhibits osteoclast differentiation by reducing nuclear factor-kappaB DNA binding and prevents in vivo bone resorption induced by receptor activator of nuclear factor-kappaB ligand and tumor necrosis factor-alpha. Free Radical Biology and Medicine 40(9): 1483-1493, 2006