Section 10
Chapter 9,323

Regulation of interleukin-12 receptor beta1 chain expression and interleukin-12 binding by human peripheral blood mononuclear cells

Wu, C.; Warrier, R.R.; Wang, X.; Presky, D.H.; Gately, M.K.

European Journal of Immunology 27(1): 147-154


ISSN/ISBN: 0014-2980
PMID: 9022011
DOI: 10.1002/eji.1830270122
Accession: 009322390

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The interleukin-12 receptor (IL-12R)beta-1 chain is an essential component of the functional IL-12R on both human T and natural killer cells. In this report it is shown that activation of human peripheral blood mononuclear cells (PBMC) with anti-CD3 monoclonal antibody (mAb) or phytohemagglutinin resulted in the up-regulation of IL-12R-beta-1 expression and IL-12 binding. Kinetic studies revealed that maximum expression of IL-12R-beta-1 and IL-12 binding occurred on days 3-4. Anti-CD3-induced expression of IL-12R-beta-1 chain and IL-12 binding by PBMC was augmented by anti-CD28 mAb, indicating that the potentiating effect of anti-CD28 on T cell responses to IL-12 could be mediated, at least in part, by the enhancement of IL-12R expression. Among 16 cytokines tested, IL-2, IL-7 and IL-15 markedly induced IL-12R-beta-1 expression and IL-12 binding on resting PBMC, whereas IL-1-alpha and tumor necrosis factor-alpha had a minimal enhancing effect. In contrast, IL-3, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, interferon (IFN)-alpha, IFN-gamma, granulocyte/macrophage colony-stimulating factor and transforming growth factor (TGF)-beta-2 had no detectable enhancing effect. AntiCD3-induced expression of IL-12R-beta-1 and of low-affinity IL-12 binding sites was partially inhibited by TGF-beta-2, IL-10 and IL-4; however, TGF-beta-2 and IL-10 completely abolished anti-CD3-induced expression of high-affinity IL-12 binding sites. Consistent with the reduction of high affinity IL-12 binding sites, PBMC activated with anti-CD3 mAb in the presence of TGF-beta-2 or IL-10 failed to produce IFN-gamma or to proliferate in response to IL-12. These results suggest that Th2 cell-derived cytokines can inhibit IL-12-induced biological functions by inhibiting IL-12R expression and that expression of a second subunit of the IL-12R (IL-12R-beta-2), required for the formation of high-affinity IL-12 binding sites, may be more highly regulated by TGF-beta-2 and IL-10 than is expression of IL-12R-beta-1.

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