Uncoupling Protein 2 Negatively Regulates Mitochondrial Reactive Oxygen Species Generation and Induces Phosphatase-Mediated Anti-Inflammatory Response in Experimental Visceral Leishmaniasis
IR@IICB: CSIR-Indian Institute of Chemical Biology, Kolkata
View Archive Info| Field | Value | |
| Title |
Uncoupling Protein 2 Negatively Regulates Mitochondrial
Reactive Oxygen Species Generation and Induces
Phosphatase-Mediated Anti-Inflammatory Response in
Experimental Visceral Leishmaniasis
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| Creator |
Ball, Writoban Basu
Kar, Susanta Mukherjee, Madhuchhanda Chande, Ajit G Mukhopadhyaya, Robin Das, Pijush K |
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| Subject |
Infectious Diseases and Immunology
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| Description |
To reside and multiply successfully within the host macrophages, Leishmania parasites impair the generation of reactive oxygen
species (ROS), which are a major host defense mechanism against any invading pathogen. Mitochondrial uncoupling proteins are
associated with mitochondrial ROS generation, which is the major contributor of total cellular ROS generation. In the present
study we have demonstrated that Leishmania donovani infection is associated with strong upregulation of uncoupling protein 2
(UCP2), a negative regulator of mitochondrial ROS generation located at the inner membrane of mitochondria. Functional
knockdown of macrophage UCP2 by small interfering RNA-mediated silencing was associated with increased mitochondrial
ROS generation, lower parasite survival, and induction of marked proinflammatory cytokine response. Induction of proinflammatory
cytokine response in UCP2 knocked-down cells was a direct consequence of p38 and ERK1/2 MAPK activation, which
resulted from ROS-mediated inhibition of protein tyrosine phosphatases (PTPs). Administration of ROS quencher, N-acetyl-Lcysteine,
abrogated PTP inhibition in UCP2 knocked-down infected cells, implying a role of ROS in inactivating PTP. Short
hairpin RNA-mediated in vivo silencing of UCP2 resulted in decreased Src homology 2 domain-containing tyrosine phosphatase 1
and PTP-1B activity and host-protective proinflammatory cytokine response resulting in effective parasite clearance. To our
knowledge, this study, for the first time, reveals the induction of host UCP2 expression during Leishmania infection to downregulate
mitochondrial ROS generation, thereby possibly preventing ROS-mediated PTP inactivation to suppress macrophage
defense mechanisms.
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| Publisher |
American Association of Immunologists
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| Date |
2011
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| Type |
Article
PeerReviewed |
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| Format |
application/pdf
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| Identifier |
http://www.eprints.iicb.res.in/2/1/iicb2.pdf
Ball, Writoban Basu and Kar, Susanta and Mukherjee, Madhuchhanda and Chande, Ajit G and Mukhopadhyaya, Robin and Das, Pijush K (2011) Uncoupling Protein 2 Negatively Regulates Mitochondrial Reactive Oxygen Species Generation and Induces Phosphatase-Mediated Anti-Inflammatory Response in Experimental Visceral Leishmaniasis. The Journal of Immunology, 187. pp. 1322-1332. ISSN 0022-1767 |
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| Relation |
http://dx.doi.org/10.4049/jimmunol.1004237
http://www.eprints.iicb.res.in/2/ |
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