Original Article

Constitutively Activated Akt-1 Is Vital for the Survival of Human Monocyte-differentiated Macrophages: Role of Mcl-1, Independent of Nuclear Factor (NF)-B, Bad, or Caspase Activation

Correspondence to: Richard M. Pope, Division of Rheumatology, Department of Medicine, Northwestern University Medical School and the VA Chicago Health Care System, Lakeside Division, 303 E. Chicago Ave., Ward 3-315, Chicago, IL 60611. Tel:312-503-8003 Fax:312-503-0994 E-mail:rmp158{at}nwu.edu.

Recent data from mice deficient for phosphatase and tensin homologue deleted from chromosome 10 or src homology 2 domain–containing 5' inositol phosphatase, phosphatases that negatively regulate the phosphatidylinositol 3-kinase (PI3K) pathway, revealed an increased number of macrophages in these animals, suggesting an essential role for the PI3K pathway for macro-phage survival. Here, we focused on the role of the PI3K-regulated serine/threonine kinase Akt-1 in modulating macrophage survival. Akt-1 was constitutively activated in human macrophages and addition of the PI3K inhibitor, LY294002, suppressed the activation of Akt-1 and induced cell death. Furthermore, suppression of Akt-1 by inhibition of PI3K or a dominant negative (DN) Akt-1 resulted in loss of mitochondrial transmembrane potential, activation of caspases-9 and -3, and DNA fragmentation. The effects of PI3K inhibition were reversed by the ectopic expression of constitutively activated Akt-1 or Bcl-x_L. Inhibition of PI3K/Akt-1 pathway either by LY294002 or DN Akt-1 had no effect on the constitutive or inducible activation of nuclear factor (NF)-B in human macrophages. However, after inhibition of the PI3K/Akt-1 pathway, a marked decrease in the expression of the antiapoptotic molecule Mcl-1, but not other Bcl-2 family members was observed, and Mcl-1 rescued macrophages from LY294002-induced cell death. Further, inhibition of Mcl-1 by antisense oligonucleotides, also resulted in macrophage apoptosis. Thus, our findings demonstrate that the constitutive activation of Akt-1 regulates macrophage survival through Mcl-1, which is independent of caspases, NF-B, or Bad.

Key Words: cell death, apoptosis, PI3K, dominant negative Akt-1, mitochondrial transmembrane potential

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