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*
Department of Pathology, Section of Immunology, University of Verona, Verona, Italy; and
The Wistar Institute, Philadelphia, PA 19104
IL-12 is a heterodimeric proinflammatory cytokine consisting of a
light 
-chain, formerly defined as p35, disulfide-linked to a heavier
ß-chain, formerly defined as p40. The ß-chain is also produced in
large excess in a free form, and disulfide-linked ß-chain homodimers
with anti-inflammatory effects are produced in the mouse. We
analyzed the biosynthesis and glycosylation of IL-12 in human
monocytes, and in a cell line stably transfected with IL-12 and ß
genes (P5-0.1). The IL-12 heterodimer and free ß-chain were
immunoprecipitated from supernatants and cell lysates of metabolically
labeled cells and resolved in SDS-PAGE. Whereas the ß-chain showed
similar pI pattern whether in the free form or associated in the
heterodimer, either in the secreted or intracellular form, the
-chain in the secreted heterodimer was much more acidic than that
present in the intracellular heterodimer. Deglycosylation experiments
with neuraminidase and Endo-F combined with two-dimensional PAGE of
single bands of the intracellular vs extracellular IL-12 heterodimer
revealed that the -chain was extensively modified with sialic acid
adducts to N-linked oligosaccharides before secretion.
N-glycosylation inhibition by tunicamycin (TM) did not
alter free ß-chain secretion, while preventing the IL-12 heterodimer
assembling and secretion. Pulse-chase experiments indicated that IL-12
persists intracellularly for a long period as an immature heterodimer,
and that glycosylation is the regulatory step that determines its
secretion. ß-chain disulfide-linked homodimers were observed in
TM-treated P5-0.1 cells, but in neither TM-treated nor untreated
monocytes.
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