Cells responsive to IL12

The major cell types that respond to IL-12 are NK cells and T cells, the latter including CD4+ and CD8+ T cells as well as 78 T cells (Figure 1). Furthermore, hematopoietic precursor cells were found to respond to IL-12 in vitro with increased proliferation and differentiation, whereas application of IL-12 in vivo leads to anemia, neutropenia and lymphopenia due to indirect effects of interferon 7 (IFN7) induced by IL-12. IL-12 has also been reported to act on activated B cells to increase immunoglobulin (Ig) secretion. Recently, murine B cells activated by crosslinking of CD40 were found to produce relatively high concentrations of IFN7 in response to a combination of IL-12 and IL-18 and this cytokine combination led to a shift in the production of IgG,/IgE to IgG2ll. The main effects of II.-12 on NK

Macrophage/DC

Bacteria Parasites Viruses -or their products

Macrophage/DC

Bacteria Parasites Viruses -or their products

Macrophage/DC

Th1 cells

Proliferation * Cytotoxicity IFNy

Proliferation CD8* T ceils-»- Cytotoxicity IFNy

Proliferation * Cytotoxicity IFNy

Proliferation IFNy

Proliferation CD8* T ceils-»- Cytotoxicity IFNy

Macrophage/DC

M HC II Ag

TCR Th1

Th1 cells

Proliferation

IFNy (TNF«, IL-2. GM-CSF) Differentiation

Proliferation IFNy

Figure 1 Stimuli that induce IL-12 production in macrophages/dendritic cells (DCs) and some of the biological effects of IL-12 on NK and T cells.

Table 2 Modulators of IL-12 production3

Positive modulators

GM-CSF:

Negative modulators IL-10:

TGFß: IL-4, IL-13: Prostaglandin E2: Phosphodiesterase inhibitor: CD46 cross-linking

Preincubation of macrophages or neutrophils

Preincubation of macrophages (DCs are generally cultivated with GM-CSF) Monocytes (human); depending on conditions the synthesis of IL-12 can also be inhibited (see below)

Potent inhibitor for macrophages and DCs, also inhibits synthesis of other cytokines (e.g. TNFa, etc.)

Strong inhibitor, also for other cytokines (e.g. TNFa, etc.)

Partial Inhibition in monocytes (human) (see above)

Leads to elevation of cAMP, inhibition of IL-12 and TNFa production

Leads to elevation of cAMP, inhibition of IL-12 and TNFa production

Induced by measles virus, dimerized C3b or antibodies to CD46

Selective inhibition of IL-12 but not of TNFa or IL-6 synthesis in human macrophages

"The results summarized in this table were mainly obtained with monocytes/macrophages as the IL-12-producing cells.

and T cells are the enhancement of cytokine production, costimulation of proliferation, and the enhancement of cytotoxic activity. Possibly most important is the induction of IFNy synthesis at different levels. In addition, the production of TNFa, granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL-2 by T cells is promoted. The importance of IL-12 for optimal IFNy production in the course of immune responses in vivo was demonstrated by the use of mice with targeted disruption of the IL-12p40 or p35 genes.

Innate resistance to infections is mediated by IL-12 that synergizes with IL-1(3 and/or TNFa in inducing IFNy production by NK cells. This proinflammatory effect of IL-12 which via IFNy leads to activation of macrophages can not only mediate protection but also pathological septic shock-like effects. The fact that IL-12 is a potent costimulator for T cells constitutes an important link between innate and acquired immunity (Figure 1).

IL-12 synergizes with T cell receptor (TCR)-stimu-

lation and with other costimuli (IL-2, CD28-ligation) in inducing IFNy production by T cells. Another important aspect of IL-12 function is the induction of differentiation of naive CD4+ T helper cells to TH1 cells. These are characterized by their high capacity to produce IFNy. Furthermore, IL-12 functions as a costimulator that synergizes with signaling via CD28 inducing IFNy production and proliferation of TH1 cells. Thus, IL-12 is generally known as the major inducer of THl-type immune responses in vitro and in vivo. However, one should notice that in the presence of small amounts of IL-4, which by itself will lead to Th2 development of naive TM cells, the addition of IL-12 does not suppress but rather enhances this Tn2 development. Such effects of IL-12 have been also observed in vivo. Injection of IL-12 into mice led to expression of IL-10 (in addition to IFNy) in not yet identified cell types. It was shown that in vitro priming of human T cells in the presence of IL-12 not only resulted in the development of cells producing IFNy but also IL-10. This would represent a feedback mech anism since IL-10 can inhibit further IL-12 synthesis by macrophages and IL-12R expression on T cells (see below).

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