A possible novel pathway of regulation by murine T helper type‐2 (T_h2) cells of a T_h1 cell activity via the modulation of the induction of nitric oxide synthase on macrophages

Abstract

Murine peritoneal macrophages activated with interferon (IFN)-gamma and lipopolysaccharide (LPS) produce high levels of nitric oxide (NO) and are efficient in killing the intracellular protozoan parasites Leishmania major in vitro. Earlier studies have shown that NO, whose synthesis in murine macrophages is catalyzed by an inducible enzyme NO synthase, plays a major effector role in the host resistance against microbial infection. We now shown that both the NO synthesis and the leishmanicidal activity can be inhibited by prior treatment of the cells with recombinant interleukin 4 (IL4). IL4 treatment had no effect on the binding of IFN-gamma to macrophages but prevented the induction of NO synthase in these cells activated with IFN-gamma and LPS. Since IFN-gamma is produced by murine T helper type-1 (Th1) cells, whereas IL4 is secreted by Th2 cells, these results suggest a novel pathway by which Th2 cells regulate an activity of Th1 cells, namely by inhibiting the induction of NO synthase. These results may also account for the mechanism by which the disease-promoting Th2 cells counteract the host-protective effect of Th1 cells in leishmaniasis and other intracellular parasitic diseases.

Induction of nitric oxide synthase gene by interleukin-1 beta in cultured rat cardiocytes.

“…Given only 1/10 contamination by nonmyocytes in our primary culture, this would strengthen the contention that cardiac myocytes are the major source of NO, and iNOS mRNA. Immunocytochemical study using specific antibody for the N-terminal fragment of mouse iNOS also shows that iNOS-like immunoreactivity is exclusively localized in cardiac myocytes, and to a lesser 33 The IL-113-induced iNOS mRNA was apparently reduced by L-NMMA with or without excess L-and D-arginine. It should be noted that Ca2-independent NOS activity but not Ca2-dependent NOS activity is increased in the myocardium from patients with dilated cardiomyopathy.44 Taking into account the present observations that cytokine can induce iNOS expression in myocardial tissues from neonatal and adult rats, the possible involvement of local production of NO by cytokine-inducible iNOS in the pathogenesis of idiopathic cardiomyopathy and acute myocarditis warrants further investigation.…”

Potentiality of Interleukin-18 as a Useful Reagent for Treatment and Prevention ofLeishmania majorInfection

“…Healing of lesions caused by L. major infection requires induction and expansion of T helper 1 (Th1) cells, which produce IFN-␥, a crucial activator of inducible nitric oxide synthase (iNOS) (5,20,23,53). In contrast, IL-4, produced by T helper 2 (Th2) cells, promotes disease, because IL-4 inhibits the expression of iNOS (25). The importance of the nitric oxide (NO)-dependent killing of intracellular parasites was demonstrated (7,9,23,24,44) and was further substantiated by the result showing that iNOS-deficient mice with a resistant background developed nonhealing cutaneous lesions (7,55).…”

Cloning and sequencing of the proximal promoter of the rat iNOS gene: activation of NFκB is not sufficient for transcription of the iNOS gene in rat mesangial cells

“…These studies were performed mainly in macrophages [8][9][10] as well as vascular smooth muscle cells (VSMCs) or MCs [11][12][13][14][15][16][17]. Most of the inhibitory effects occur at the transcriptional level.…”