IL-4 inhibits H2O2 production and antileishmanial capacity of human cultured monocytes mediated by IFN-gamma.

Abstract

The effect of IL-4 on the IFN-gamma-induced state of activation of cultured human monocytes was investigated with regard to their ability to produce hydrogen peroxide and their antileishmanial capacity towards the intracellular parasite Leishmania donovani. IL-4 was found to inhibit the IFN-gamma-dependent hydrogen peroxide production of monocytes. Treatment of monocytes with IFN-gamma (200 to 600 U/ml) for 48 h increased the hydrogen peroxide production fourfold above background. Coincubation of the monocytes with IL-4 (1 to 1000 U/ml) and IFN-gamma (200 to 600 U/ml) inhibited this increase by 50 to 100%. IL-4 alone did not modulate the hydrogen peroxide production of monocytes. Pretreatment of monocytes with IL-4 for 20 min to 3 h was already effective in preventing the IFN-gamma response. Addition of IL-4 not later than 6 h after the start of incubation with IFN-gamma was necessary for an optimal inhibitory effect. IL-4 also inhibited the IFN-gamma-induced antileishmanial capacity of monocytes: IFN-gamma (1000 U/ml) induced a 54 +/- 10% reduction in the number of parasites. Monocytes treated with combinations of IL-4 (100 to 1000 U/ml) and IFN-gamma (1000 U/ml) were unable to reduce the parasite numbers. IL-4 alone did not alter the uptake of Leishmania donovani nor induce antileishmanial activity. These results demonstrate that IL-4 disables human cultured monocytes to respond to IFN-gamma activation.

Phlebotomus papatasiSand Fly Salivary Gland Lysate Down-Regulates a Th1, but Up-Regulates a Th2, Response in Mice Infected withLeishmania major

“…In resistant mice (e.g., CBA), IFN-␥ is the principal mediator of resistance to L. major due to its ability to activate macrophages (M) 4 to destroy the parasite (12)(13)(14)(15), and treating mice with a neutralizing anti-IFN-␥ Ab exacerbates the course of infection by promoting the outgrowth of Th2 cells (16,17). In susceptible mice (BALB/c), IL-4 can block the ability of IFN-␥ to activate M to destroy Leishmania (18,19), and treating mice with a neutralizing anti-IL-4 Ab allows the animals to cure their infection by promoting the outgrowth of Th1 cells (20,21). In addition, other cells of the immune system, such as M, can produce cytokines and factors (e.g., IL-10, IL-12, nitric oxide (NO), and TGF-␤) that can modulate an immune response and influence the outcome of infection with L. major in mice (7)(8)(9)(10)(11).…”

Paired Stat6 C-Terminal Transcription Activation Domains Required Both for Inhibition of an IFN-Responsive Promoter andTrans-Activation

“…Accordingly, it is important to understand the mechanisms by which different signals are integrated. IL-4 frequently antagonizes the actions of IFN-␥, and this reciprocal antagonism extends to transcription regulation (13)(14)(15)(16)(17). The molecular mechanisms which account for IL-4 inhibition of the transcriptional activity induced by IFN-␥, and for the integration of IFN-␥-and IL-4activated signaling pathways, are not well understood.…”

“…Similar transcriptional antagonism is mediated by IL-4 against IFN-␥. Thus, IL-4 inhibits the induction of the IL-12R␤2 chain, IFN-␥-induced high-affinity IgG receptor (Fc␥RI), and IFN-␥-enhanced Ig class switching to the C␥2a H chain locus (13)(14)(15)(16)(17). Taken together, these findings suggest the existence of mechanisms by which IL-4 inhibits IFN-␥-inducible genes.…”

“…Certain IFN-␥-dependent responses are enhanced in IL-4-deficient mice, and a number of specific target genes induced by IFN-␥ or other stimuli have previously been shown to be subject to inhibition by IL-4 (13)(14)(15)(16)(42)(43)(44). The IRF-1 gene is IFN-␥ inducible, involved in the differentiation of Th function, and has a well-characterized promoter that mimics regulation of the endogenous gene (36,41,(45)(46)(47).…”

“…Although, the basis for these reciprocal effects of cytokines is unclear, transcriptional antagonism between IL-4 and IFN-␥ has been amply documented (Refs. [10][11][12][13][14][15][16]reviewed in Ref. 17).…”