Journal
FASEB JOURNAL
Volume 28, Issue 7, Pages 3050-3063Publisher
FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.13-245126
Keywords
ecotin; Toll; interferon; ISP2
Categories
Funding
- Fundacao de Amparo a Pesquisa do Estado do Rio de Janeiro (FAPERJ
- Portuguese Research Foundation of Rio de Janeiro)
- Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq
- National Council for Technological and Scientific Development)
- Wellcome Trust [085349]
Ask authors/readers for more resources
In cutaneous leishmaniasis, Leishmania amazonensis activates macrophage double-stranded, RNA-activated protein kinase R (PKR) to promote parasite growth. In our study, Leishmania major grew normally in RAW cells, RAW-expressing dominant-negative PKR (PKR-DN) cells, and macrophages of PKR-knockout mice, revealing that PKR is dispensable for L. major growth in macrophages. PKR activation in infected macrophages with poly I: C resulted in parasite death. Fifty percent of L. major-knockout lines for the ecotin-like serine peptidase inhibitor (ISP2; Delta isp2/isp3), an inhibitor of neutrophil elastase (NE), died in RAW cells or macrophages from 129Sv mice, as a result of PKR activation. Inhibition of PKR or NE or neutralization of Toll-like receptor 4 or 2(TLR4 or TLR2) prevented the death of Delta isp2/isp3. Delta isp2/isp3 grew normally in RAW-PKR-DN cells or macrophages from 129Sv pkr(-/-), tlr2(-/-), trif(-/-), and myd88(-/-) mice, associating NE activity, PKR, and TLR responses with parasite death. Delta isp2/isp3 increased the expression of mRNA for TNF-alpha by 2-fold and of interferon beta (IFN beta) in a PKR-dependent manner. Antibodies to TNF-alpha reversed the 95% killing by Delta isp2/isp3, whereas they grew normally in macrophages from IFN receptor-knockout mice. We propose that ISP2 prevents the activation of PKR via an NE-TLR4-TLR2 axis to control innate responses that contribute to the killing of L. major.
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