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Secretion and not Restricted to T and NK Cells
Preclinical Research and Development, Genetics Institute, Andover, MA 01810
The biological response to IL-12 is mediated through specific
binding to a high affinity receptor complex composed of at least two
subunits (designated IL-12Rß1 and IL-12Rß2) that are expressed on
NK cells and activated T cells. The selective loss of IL-12Rß2
expression during Th2 T cell differentiation suggests that regulation
of this receptor component may govern IL-12 responsiveness. In murine
assays, down-regulation of IL-12Rß2 expression can be prevented by
treatment with IFN-
, indicating that receptor expression and hence
IL-12 responsiveness may be regulated, at least in part, by the local
cytokine milieu. In this study, we report that cellular expression of
both IL-12Rß1 and ß2 mRNA is increased in the lymph nodes of naive
mice following systemic administration of murine rIL-12 (rmIL-12).
Changes in IL-12R mRNA were associated with increased IFN- secretion
following ex vivo activation of lymph node cells with rmIL-12,
indicating the presence of a functional receptor complex. Expression of
IL-12R mRNA was not restricted to lymph node T cells, and its autocrine
regulation was independent of secondary IFN- secretion. Data from
fractionated lymph node cells as well as rmIL-12-treated B
cell-deficient mice suggest that IL-12-responsive B cells may represent
an alternative cellular source for IFN- production. However, the
strength of the biological response to rmIL-12 is not governed solely
by receptor expression, as rmIL-12-induced IFN- secretion from
cultured lymph node cells is accessory cell dependent and can be
partially blocked by inhibition of B7
costimulation.
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