Enhanced NF-kappaB activation and cellular function in macrophages lacking IkappaB kinase 1 (IKK1).

Qiutang Li, Qingxian Lu, Virginie Bottero, Gabriela Estepa, Lisa Morrison, Frank Mercurio, Inder M Verma

The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.

Proceedings of the National Academy of Sciences of the United States of America 2005 Aug 30

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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.

Citation

Qiutang Li, Qingxian Lu, Virginie Bottero, Gabriela Estepa, Lisa Morrison, Frank Mercurio, Inder M Verma. Enhanced NF-kappaB activation and cellular function in macrophages lacking IkappaB kinase 1 (IKK1). Proceedings of the National Academy of Sciences of the United States of America. 2005 Aug 30;102(35):12425-30