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The Journal of Immunology, Vol 157, Issue 1 305-312, Copyright © 1996 by American Association of Immunologists


ARTICLES

IFN-alpha beta reconstitutes the deficiency in lipid A-activated AKR macrophages for nitric oxide synthase

H Jiang, JA Rummage, A Zhou, Z Chen, MJ Herriot, CA Stewart, M Kolosov and RW Leu
Oklahoma Medical Research Foundation, Noble Center for Biomedical Research, Oklahoma City 73104, USA.

AKR mouse peritoneal macrophages (PM) were previously found to have a defect in their response to lipid A for nitric oxide (NO)-mediated tumor cytotoxicity, which was related to a lower level of C1q synthesis and reconstituted by exogenous IFN-gamma or C1q. We used AKR-PM as a model to further define the role of IFN-alpha beta in modulation of induction of macrophage nitric oxide synthase (NOS) in response to lipid A. Studies have revealed that AKR-PM produced a significantly lower level of IFN-alpha beta than responsive C3H-PM in response to lipid A. AKR-PM failed to increase NOS mRNA synthesis and NO generation when exposed to lipid A, although they had normal levels of TNF-alpha bioactivity and mRNA expression. This partial deficiency of AKR-PM to lipid A stimulation was reconstituted completely by exogenous IFN-alpha beta for both synthesis of NOS mRNA and release of NO. The failure of AKR-PM to produce NOS to lipid A stimulation appears to be related to reduced secretion of IFN-alpha beta and the resultant failure to express TNF-alpha type II receptor (TNF-RII) mRNA, which in turn decreases TNF-alpha binding to its receptor for autocrine induction of NOS. Insufficient synthesis and secretion of endogenous IFN-alpha beta may be the primary reason for AKR-PM refractoriness to induction of NOS in response to lipid A. furthermore, the close correlation between lack of IFN-alpha beta secretion and decreased TNF-RII mRNA synthesis may implicate a critical role for IFN-alpha beta in the upregulation of macrophage TNF-RII receptor expression for autocrine induction of NOS during lipid A stimulation.


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E. Lopez-Collazo, S. Hortelano, A. Rojas, and L. Bosca
Triggering of Peritoneal Macrophages with IFN-{alpha}/{beta} Attenuates the Expression of Inducible Nitric Oxide Synthase Through a Decrease in NF-{kappa}B Activation
J. Immunol., March 15, 1998; 160(6): 2889 - 2895.
[Abstract] [Full Text] [PDF]




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