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1 Physiology, Temple University School of Medicine, Philadelphia, PA, USA
* To whom correspondence should be addressed. E-mail: mautieri{at}temple.edu.
Allograft Inflammatory Factor-1 (AIF-1) is a cytoplasmic, calcium-binding, inflammation-responsive scaffold protein. Several studies have reported increased AIF-1 expression in activatied macrophages, and have implicated AIF-1 as a marker of activated macrophages. However the function of AIF-1 in macrophages, and the mechanism whereby it participtes in macrophage activation is unknown at this time. Immunohistochemical analysis co-localized AIF-1 expression with CD68-positive macrophages in atherosclerotic human coronary arteries. Subsequent experiments were designed to determine a role for AIF-1 in macrophage activation in response to atherogenic stimuli. Stimulation of human and murine macrophages with oxidized LDL significantly increased AIF-1 expression above basal levels. Stable transfection of AIF-1 siRNA in macrophages reduced AIF-1 protein expression by 79%, and reduced macrophage proliferation by 52% (P<0.01). Inhibition of proliferation was not due to induction of apoptosis. Sequences which did not knock down AIF-1 expression had no effect on proliferation. AIF-1 siRNA expression reduced macrophage migration by 60% (P<0.01). Both proliferation and migration of siRNA expressing macrophages could be restored by adenoviral expression of AIF-1 (P<0.001 and 0.005, respectively), suggesting a tight association between AIF-1 expression and macrophage activation. Phosphorylation of Akt, p44/42 MAPK, and p38 kinase were significantly reduced in siRNA macrophages challenged with oxidized LDL (P<0.05). Phosphorylation of p38 kinase was significantly inhibited in siRNA macrophages stimulated with T lymphocyte conditioned media (P<0.05). These data indicate that AIF-1 mediates atherogenic-initiated signaling and activation of macrophages.
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