Enhanced NF-kappaB activation and cellular function in macrophages lacking IkappaB kinase 1 (IKK1).
IkappaB kinase (IKK) complex plays a key regulatory role in macrophages for NF-kappaB activation during both innate and adaptive immune responses. Because IKK1-/- mice died at birth, we differentiated functional macrophages from embryonic day 15.5 IKK1 mutant embryonic liver. The embryonic liver-derived macrophage (ELDM) showed enhanced phagocytotic clearance of bacteria, more efficient antigen-presenting capacity, elevated secretion of several key proinflammatory cytokines and chemokines, and known NFkappaB target genes. Increased NFkappaB activity in IKK1 mutant ELDM was the result of prolonged degradation of IkappaBalpha in response to infectious pathogens. The delayed restoration of IkappaBalpha in pathogen-activated IKK1-/- ELDM was a direct consequence of uncontrolled IKK2 kinase activity. We hypothesize that IKK1 plays a checkpoint role in the proper control of IkappaBalpha kinase activity in innate and adaptive immunity.
Li
Qiutang
Q
The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
Lu
Qingxian
Q
Bottero
Virginie
V
Estepa
Gabriela
G
Morrison
Lisa
L
Mercurio
Frank
F
Verma
Inder M
IM
D000818:Animals; D017951:Antigen Presentation; D018925:Chemokines / Q000096:biosynthesis; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D051550:I-kappa B Kinase; D020672:I-kappa B Proteins / Q000378:metabolism; D066298:In Vitro Techniques; D018836:Inflammation Mediators / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D010587:Phagocytosis; D010766:Phosphorylation; D011247:Pregnancy; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency* / Q000235:genetics
D018925:Chemokines; D016207:Cytokines; D020672:I-kappa B Proteins; D018836:Inflammation Mediators; D016328:NF-kappa B; C000606205:Nfkbia protein, mouse; D000072000:NF-KappaB Inhibitor alpha; D017346:Protein Serine-Threonine Kinases; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase; C496562:Ikbkb protein, mouse; C496566:Ikbke protein, mouse