IL-4 Induces In Vivo Production of IFN-γ by NK and NKT Cells

Abstract

Although IL-4 and IFN-γ often have opposite effects and suppress each other’s production by T cells, IL-4 can stimulate IFN-γ production. To characterize this, we injected mice with IL-4 and quantified IFN-γ production with the in vivo cytokine capture assay. IL-4 induced Stat6-dependent IFN-γ production by NK and, to a lesser extent, NKT cells, but not conventional T cells, in 2–4 h. Increased IFN-γ production persisted at a constant rate for >24 h, but eventually declined, even with continuing IL-4 stimulation. This eventual decline in IFN-γ production was accompanied by a decrease in NK and T cell numbers. Consistent with a dominant role for NK cells in IL-4-stimulated IFN-γ secretion, IL-4 induction of IFN-γ was B and T cell-independent; suppressed by an anti-IL-2Rβ mAb that eliminates most NK and NKT cells; reduced in Stat4-deficient mice, which have decreased numbers of NK cells; and absent in Rag2/γc-double-deficient mice, which lack T, B, and NK cells. IL-4-induced IFN-γ production was not affected by neutralizing IL-12p40 and was increased by neutralizing IL-2. IL-13, which signals through the type 2 IL-4R and mimics many IL-4 effects, failed to stimulate IFN-γ production and, in most experiments, suppressed basal IFN-γ production. Thus, IL-4, acting through the type 1 IL-4R, induces Stat6-dependent IFN-γ secretion by NK and NKT cells. This explains how IL-4 can contribute to Th1 cytokine-associated immune effector functions and suggests how IL-13 can have stronger proallergic effects than IL-4.

The effect of in vivo exposure to zearalenone on cytokine secretion by Th1 and Th2 lymphocytes in porcine Peyer’s patches after in vitro stimulation with LPS

“…Interestingly, IFN-γ was co-secreted with the antagonistic IL-4 on day 42 in group C, but the above was not observed in cell culture supernatants in group E. According to Morris et al (2006), activated NKT cells can secrete both IL-4 and IFN-γ, and selected populations of CD8+ Tc lymphocytes produce IFN-γ (Tc1) and IL-4 (Tc2) (Romagnani 1996, Seder et al 1996. The above suggests that a cellular immune response was developed in control cultures where immunocompetent cells had not been exposed to ZEN in vivo.…”

STAT6-mediated suppression of erythropoiesis in an experimental model of malarial anemia

“…26 Evidence indicates that IL-4, but not IL-13, acts via a STAT6-dependent mechanism to induce IFN-γ production by natural killer cells and natural killer T cells; 44 IL-4-induced IFN-γ production has been demonstrated in mice infected with Candida albicans and Leishmania major. 45,46 As observed in STAT6 -/-mice, IL-4 neutralization in P. chabaudi-infected WT mice resulted in a similar course of anemia despite a significantly higher peak parasitemia compared to that in isotype control WT mice.…”

A natural protective function of invariant NKT cells in a mouse model of innate‐cell‐driven lung inflammation

“…Finally, we cannot exclude a role for IL-4, a cytokine produced during IL-33-mediated lung inflammation (Supporting Information Fig. 4) that has been described to drive IFN-g production by iNKT cells in vivo [29].…”