J Biol Chem 2002 Feb 5;
Nguyen VT, Benveniste EN.
Department of Cell Biology, University of Alabama at Birmingham, Birmingham, AL 35294-0005.
CD40 is a member of the TNF-receptor superfamily.
CD40 expression on antigen presenting cells (including macrophages and microglia) is crucial for T-cell activation.
Aberrant expression of CD40 has been associated with autoimmune inflammatory diseases such as multiple sclerosis and rheumatoid arthritis.
We have recently shown that the cytokine IFN-[gamma] is the most potent inducer of CD40 expression in macrophages and microglia, and this induction is mediated by the IFN-[gamma]-activated transcription factor STAT-1[alpha] and constitutively expressed PU.1 and/or Spi-B.
In this study, we have discovered that a major component of IFN-[gamma]-induced CD40 expression involves the endogenous production of the cytokine TNF-[alpha].
The inclusion of anti-TNF-[alpha] neutralizing antibody significantly inhibits IFN-[gamma]-induced CD40 mRNA and CD40 promoter activity.
IFN-[gamma] induced CD40 protein expression is attenuated in TNF-[alpha] deficient microglia, and can be restored with exogenous TNF-[alpha].
Site-directed mutagenesis studies demonstrate that three of the four NF-[kappa]B elements in the CD40 promoter are required for IFN-[gamma]-induced CD40 promoter activity. IFN-[gamma] treatment leads to the activation of NF-[kappa]B in a time-dependent manner, which is inhibited in the presence of anti-TNF-[alpha] neutralizing antibody.
These results indicate that IFN-[gamma]-induced TNF-[alpha] production and subsequent NF-[kappa]B activation are an integral part of the mechanism of IFN-[gamma]-induced CD40 expression.