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Interferon- -Dependent Inducible Expression of the Human
Interleukin-12 p35 Gene in Monocytes Initiates From a TATA-Containing
Promoter Distinct From the CpG-Rich Promoter Active in
Epstein-Barr Virus-Transformed Lymphoblastoid Cells
Mark P. Hayes,
Finbarr J. Murphy, and
Parris R. Burd
From the Division of Cytokine Biology and Division of Cellular and
Gene Therapies, Center for Biologics Evaluation and Research, Food and
Drug Administration, Rockville, MD.
Interleukin-12 (IL-12) production by human monocytes is stringently
regulated through the inducibility of both subunits, p35 and p40, and
expression of p35 mRNA is the limiting factor for the secretion of the
bioactive IL-12 p70 heterodimer. Optimal induction of p35 mRNA requires
priming of the monocytes by interferon- (IFN-), followed by brief
exposure to lipopolysaccharide or other bacterial products. To
investigate control of p35 gene expression, we isolated genomic clones
containing the human p35 gene and determined the 5 end of the
mRNA expressed in monocytes. We discovered that a unique p35 transcript
is induced in monocytes that begins downstream of a consensus TATA box
that lies within the 5 end of the cDNA originally cloned from
Epstein-Barr virus (EBV)-transformed B cells. Analysis of p35 mRNA by
Northern blotting showed that the message from monocytes is
approximately 200 bases shorter than message derived from the
EBV-transformed B-cell line VDS. The initiation sites downstream from
the TATA box were confirmed by RNase protection and 5 RACE. The
data indicate that p35 transcription can initiate from different sites
depending on the cell type and that the shorter inducible transcript in
monocytes is the one that accumulates after stimulation. Protein
translation of these two forms may result in proteins of different
sizes with potential implications for the regulation of IL-12 secretion
and function.
Blood, Vol. 91 No. 12 (June 15), 1998:
pp. 4645-4651
© 1998 by The American Society of Hematology.
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