Journal
EUROPEAN JOURNAL OF IMMUNOLOGY
Volume 39, Issue 3, Pages 741-751Publisher
WILEY-BLACKWELL
DOI: 10.1002/eji.200838465
Keywords
Cystatin; Leishmaniasis; Macrophage; Nitric oxide; Signal transduction
Categories
Funding
- Council of Scientific and Industrial Research, Government of India [NWP 0038]
Ask authors/readers for more resources
Curative effect of cystatin, a natural cystein protease inhibitor, on experimental visceral leishmaniasis was associated with strong upregulation of iNOS. The transductional mechanisms underlying this cellular response was investigated in the murine macrophage cell line RAW 264.7 and in the BALB/c mouse model of visceral leishmaniasis. Cystatin synergizes with IFN-gamma in inducing ERK1/2 phosphorylation and NF-kappa B DNA-binding activity. Pretreatment of cells with specific inhibitors of NF-kappa B or ERK1/2 pathway blocked the cystatin plus IFN-gamma-inducible NF-kappa B activity and markedly reduced the expression of iNOS at both mRNA and protein levels. Silencing of mitogen- and stress-activated protein kinase 1 significantly reduced cystatin-mediated NF-kappa B-dependent iNOS gene transcription suggesting the involvement of mitogen- and stress-activated protein kinase 1 activation in ERK1/2 signaling. DNA binding as well as silencing experiments revealed the requirement of IFN-gamma-mediated JAK-STAT activation even though cystatin did not modulate this signaling cascade by itself. In the in vivo situation, key steps in the activation cascade of NF-kappa B, including nuclear translocation of NF-kappa B subunits, I kappa B phosphorylation and I kappa B kinase, are all remarkably enhanced in Leishmania-infected mice by cystatin. Understanding the molecular mechanisms through which cystatin modulates macrophage effector responses will contribute to better define its potential for macrophage-associated diseases, in general.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available