IKK-i signals through IRF3 and NFkappaB to mediate the production of inflammatory cytokines.
IKK-i and TBK1 were recently identified as IKK-related kinases that are activated by toll-like receptors TLR3 and TLR4. These kinases were identified as essential components of the virus-activated as well as LPS-MyD88 independent kinase complex that phosphorylates IRF3 and results in the production of cytokines involved in innate immunity. Both IKK-i and TBK1 have also been implicated in the activation of the NFkappaB pathway but the precise mechanism is not clear. Although the literature to date suggests that IKK-i and TBK1 play redundant roles in TLR3 and TLR4 signaling, recent data suggest that there may be subtle differences in the signaling pathways affected by these kinases. We have generated tetracycline-inducible stable cell lines that express a wild type or kinase-inactive mutant form of IKK-i. Our data suggest that expression of IKK-i can activate both NFkappaB and IRF3, leading to the production of several cytokines including interferon beta. IKK-i most likely acts upstream of IKK2 to activate NFkappaB in these cells since expression of the kinase-inactive version of IKK-i did not inhibit TNFalpha mediated production of inflammatory cytokines. The data suggest that IKK-i is not involved in TNF-alpha mediated signaling but instead could likely play a role in activating IKK2 downstream of Toll-like receptor signaling. We also identified STAT1, Tyk2, and JAK1 as secondary mediators of IKK-i signaling as a result of interferon beta production in these cells.
Sankar
Sabita
S
Experimental Therapeutics (Inflammation), Celgene, 4550 Towne Centre Court, San Diego, CA 92121, United States. ssankar@celgene.com
Chan
Henry
H
Romanow
William J
WJ
Li
Jianwu
J
Bates
R J
RJ
D002460:Cell Line; D018946:Chemokine CCL5 / Q000096:biosynthesis; D054357:Chemokine CXCL10; D019743:Chemokines, CXC / Q000096:biosynthesis; D016207:Cytokines / Q000096:biosynthesis*; D004268:DNA-Binding Proteins / Q000378:metabolism; D004789:Enzyme Activation; D006801:Humans; D051550:I-kappa B Kinase; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism / Q000502:physiology*; D016899:Interferon-beta / Q000096:biosynthesis; D016209:Interleukin-8 / Q000096:biosynthesis; D053613:Janus Kinase 1; D009154:Mutation; D016328:NF-kappa B / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D053634:TYK2 Kinase; D013752:Tetracycline / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
D018946:Chemokine CCL5; D054357:Chemokine CXCL10; D019743:Chemokines, CXC; D016207:Cytokines; D004268:DNA-Binding Proteins; C494232:IRF3 protein, human; D050838:Interferon Regulatory Factor-3; D016209:Interleukin-8; D016328:NF-kappa B; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D014409:Tumor Necrosis Factor-alpha; D016899:Interferon-beta; D011505:Protein-Tyrosine Kinases; C507904:JAK1 protein, human; D053613:Janus Kinase 1; D053634:TYK2 Kinase; C070139:TYK2 protein, human; D017346:Protein Serine-Threonine Kinases; D051550:I-kappa B Kinase; D013752:Tetracycline