Reactome: A Curated Pathway Database

Stimulation of IL6 transcription in senescent cells (R-HSA-3790130)

Species Homo sapiens


Methylation of the IL6 promoter by EHMT1:EHMT2 (GLP:G9a) histone methyltransferases inhibits IL6 transcription, while Cdh1:APC/C-mediated degradation of EHTM1:EHTM2 downstream of the ATM-TP53-CDKN1A axis stimulates IL6 transcription (Takahashi et al. 2012). Oncogenic RAS signaling stimulates activation of the CEBPB transcription factor (C/EBP-beta) which binds IL6 promoter and stimulates IL6 transcription (Kuilman et al. 2008, Lee et al. 2010). NF kappa B transcription factor is also activated in senescent cells (Chien et al. 2011) through interleukin-1-alpha (IL1A) signaling (Jimi et al. 1996, Hartupee et al. 2008, Orjalo et al. 2009), and it cooperates with CEBPB in the activation of IL6 transcription (Shimizu et al. 1990, Libermann and Baltimore 1990, Matsusaka et al. 1993, Acosta et al. 2008). Autocrine IL6 signaling stimulates CEBPB expression (Kuilman et al. 2008), creating a positive feedback loop. STAT3, activated by IL6 signaling cascade is necessary for CEBPB transcription, but the direct binding of STAT3 to the CEBPB promoter has not been demonstrated (Niehof et al. 2001).

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Compartment extracellular region , nucleoplasm
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Literature References
pubMedId Title Journal Year
22178396 DNA damage signaling triggers degradation of histone methyltransferases through APC/C(Cdh1) in senescent cells Mol. Cell 2012
18555778 Oncogene-induced senescence relayed by an interleukin-dependent inflammatory network Cell 2008
20351173 RSK-mediated phosphorylation in the C/EBP{beta} leucine zipper regulates DNA binding, dimerization, and growth arrest activity Mol. Cell. Biol. 2010
20452968 CCAAT/Enhancer-binding protein beta DNA binding is auto-inhibited by multiple elements that also mediate association with p300/CREB-binding protein (CBP) J. Biol. Chem. 2010
11114305 Interleukin-6-induced tethering of STAT3 to the LAP/C/EBPbeta promoter suggests a new mechanism of transcriptional regulation by STAT3 J. Biol. Chem. 2001
21979375 Control of the senescence-associated secretory phenotype by NF-?B promotes senescence and enhances chemosensitivity Genes Dev. 2011
18555777 Chemokine signaling via the CXCR2 receptor reinforces senescence Cell 2008
8234276 Transcription factors NF-IL6 and NF-kappa B synergistically activate transcription of the inflammatory cytokines, interleukin 6 and interleukin 8 Proc. Natl. Acad. Sci. U.S.A. 1993
2405250 Involvement of a NF-kappa B-like transcription factor in the activation of the interleukin-6 gene by inflammatory lymphokines Mol. Cell. Biol. 1990
2183031 Activation of interleukin-6 gene expression through the NF-kappa B transcription factor Mol. Cell. Biol. 1990
8617720 Interleukin-1 alpha activates an NF-kappaB-like factor in osteoclast-like cells J. Biol. Chem. 1996
18411265 Interleukin 1alpha-induced NFkappaB activation and chemokine mRNA stabilization diverge at IRAK1 J. Biol. Chem. 2008
19805069 Cell surface-bound IL-1alpha is an upstream regulator of the senescence-associated IL-6/IL-8 cytokine network Proc. Natl. Acad. Sci. U.S.A. 2009