title: TGF-β-regulated tyrosine phosphatases induce lymphocyte apoptosis in Leishmania donovani-infected hamsters.
abstract: Visceral leishmaniasis, which is caused by Leishmania donovani, is one of the major health problems of the Indian subcontinent. Infected hosts have been reported to have impaired lymphoproliferation. However, the fate of anergic cells is still elusive. In the present investigation, L. donovani-infected hamsters were used to study the mechanism of lymphocyte cell death. Lymph node-derived lymphocytes were analysed for apoptotic death through mitochondrial abnormality, caspase activity and DNA degradation. The data demonstrate that the disease progression leads to a gradual impairment of lymphocyte proliferation in the presence of Concanavalin A. The fate of the anergic lymphocytes is intrinsic apoptosis, which is evident by the depolarization of the mitochondrial membrane potential, cytosolic release of cytochrome c, caspase activation and DNA fragmentation. Tumour growth factor (TGF)-β, which is secreted by macrophages, was significantly upregulated in the lymph node compartment of infected hamsters. Adding a neutralizing TGF-β antibody and a recombinant TGF-β resulted in the downregulation and induction of lymphocyte apoptosis, respectively. Furthermore, it has been observed that TGF-β triggers the apoptotic death of lymphocytes through the upregulation of tyrosine phosphatase activity and that the use of sodium orthovanadate (Na(3)VO(4), a tyrosine phosphatase inhibitor) reduces the apoptotic frequency. Thus, this study clearly reports the novel involvement of tyrosine phosphatases in TGF-β-induced lymphocyte apoptosis in Leishmania-infected hamsters.
authors.affiliation: Division of Molecular Biology, [corrected] Rajendra Memorial Research Institute of Medical Sciences, Agamkuan, Patna, Bihar, India.
authors.forename: Rajdeep
authors.initials: R
authors.lastname: Banerjee
authors.forename: Sudeep
authors.initials: S
authors.lastname: Kumar
authors.forename: Abhik
authors.initials: A
authors.lastname: Sen
authors.forename: Ananda
authors.initials: A
authors.lastname: Mookerjee
authors.forename: Piyali
authors.initials: P
authors.lastname: Mukherjee
authors.forename: Syamal
authors.initials: S
authors.lastname: Roy
authors.forename: Subrata
authors.initials: S
authors.lastname: Pal
authors.forename: Pradeep
authors.initials: P
authors.lastname: Das
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D006224:Cricetinae; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000276:immunology; D007893:Leishmania donovani / Q000276:immunology; D007898:Leishmaniasis, Visceral / Q000201:enzymology / Q000503:physiopathology*; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D008214:Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D008928:Mitochondria / Q000276:immunology / Q000378:metabolism; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000276:immunology; D015854:Up-Regulation / Q000276:immunology; D014638:Vanadates / Q000494:pharmacology
chemical_list: D057134:Antibodies, Neutralizing; D004791:Enzyme Inhibitors; D016212:Transforming Growth Factor beta; D014638:Vanadates; D017027:Protein Tyrosine Phosphatases