Phorbol esther-induced differentiation in human macrophages reveals the existence of factors destabilizing MHC class II transactivator (CIITA) mRNA

The human promyelocytic U937 and THP1 cell lines express
detectable levels of MHC class II (MHC-II) molecules.
Treatment with 12-O-tetradecanoyl phorbol 13-acetate (TPA),
inducing macrophage-like differentiation, produces a dramatic
decrease of MHC-II expression as result of down-modulation
of the AIR-1-encoded MHC-II transcriptional activator CIITA.
This event is specific, as MHC-I remains unaffected. Similar
results are observed with U937 cells expressing an exogenous
full length CIITA. Molecular studies demonstrate that TPA
treatment affects the stability of CIITA mRNA rather than
CIITA transcription. In fact the destabilizing function of
CIITA 30 untranslated region (UTR) may be transferred also
on EGFP reporter cDNA. By this analysis, it is shown that
cis–acting elements, within the distal 650 bp of the 1035 bp 30
UTR, are associated to transcript instability. Transcription inhibitors
actinomycin-D and 5,6-dichlororibofuranosyl benzimidazole,
and the translation inhibitor cycloheximide significantly
rescue the accumulation of CIITA mRNA in TPA-treated cells.
A similar effect is also observed after treatment with staurosporine
and the PKC-specific inhibitor GF109203X. The instability of
CIITA mRNA produced by TPA in U937 is not seen in B cells.
These results demonstrate the presence of an additional level of
control of MHC-II expression in the macrophage cell lineage
depending upon the control of CIITA mRNA stability most
likely mediated by differentiation-induced, 30UTR-interacting factors
which require kinase activity for their destabilizing function.
Instability of CIITA mRNA during differentiation toward antigen
presenting (APC) function should be a novel, intriguing
negative feedback to avoid redundancy in the triggering of T
helper responses.