Nitric oxide inhibits INFgamma-induced increases in CIITA mRNA abundance and activation of CIITA dependent genes—class II MHC, Ii and H-2M. Class II TransActivator

M L Kielar, S C Sicher, J G Penfield, D R Jeyarajah, C Y Lu
Inflammation 2000, 24 (5): 431-45

BACKGROUND: Nitric oxide (NO) has been recently implicated as a powerful inhibitor of immune responses during allograft rejection, and some autoimmune and infectious diseases. We previously showed that one potential regulatory effect of NO is inhibition of IFNgamma-stimulated expression of Class II MHC on macrophages. Activation of this gene is mediated by the "Class II TransActivator" (CIITA). We now ask whether NO inhibits CIITA and thus the family of genes regulated by CIITA--Class II MHC, Ii, and H-2M. The latter two genes participate in antigen processing and formation of the cell-surface peptide-Class II MHC complex.

METHODS: Murine macrophages--both peritoneal macrophages and the RAW264.7 macrophage line--were stimulated in vitro with IFNgamma. NO production was measured by the Greiss reagent. Transcription of Class II MHC was measured by nuclear run-on assay. mRNA abundance of Class II MHC, Ii, H-2M, and CIITA was measured by Northern blotting and RT-PCR.

RESULTS: NO inhibits IFNgamma-induced increases in the abundance and transcription of the Class II MHC Ab gene. The increases in mRNA abundance of CIITA, Ii, and H-2M are also inhibited. As a control, we found that NO did not inhibit LPS-induce increases in TNFalpha mRNA abundance.

CONCLUSIONS: NO inhibits IFNgamma-induced increases in CIITA, and thus inhibits the CIITA-regulated genes: Class II MHC, Ii, and H-2M. Early during rejection, NO production by macrophages may result after stimulation by IFNgamma produced by CD4+ T cells, and be an effector of allograft damage. High concentrations of NO may then act as a feedback inhibitor which decreases antigen presentation by macrophages and thus decreases CD4 T cell activation.

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