title: Growth factor and Th2 cytokine signaling pathways converge at STAT6 to promote arginase expression in progressive experimental visceral leishmaniasis.
abstract: Host arginase 1 (arg1) expression is a significant contributor to the pathogenesis of progressive visceral leishmaniasis (VL), a neglected tropical disease caused by the intracellular protozoan Leishmania donovani. Previously we found that parasite-induced arg1 expression in macrophages was dependent on STAT6 activation. Arg1 expression was amplified by, but did not require, IL-4, and required de novo synthesis of unknown protein(s). To further explore the mechanisms involved in arg1 regulation in VL, we screened a panel of kinase inhibitors and found that inhibitors of growth factor signaling reduced arg1 expression in splenic macrophages from hamsters with VL. Analysis of growth factors and their signaling pathways revealed that the Fibroblast Growth Factor Receptor 1 (FGFR-1) and Insulin-like Growth Factor 1 Receptor (IGF-1R) and a number of downstream signaling proteins were activated in splenic macrophages isolated from hamsters infected with L. donovani. Recombinant FGF-2 and IGF-1 increased the expression of arg1 in L. donovani infected hamster macrophages, and this induction was augmented by IL-4. Inhibition of FGFR-1 and IGF-1R decreased arg1 expression and restricted L. donovani replication in both in vitro and ex vivo models of infection. Inhibition of the downstream signaling molecules JAK and AKT also reduced the expression of arg1 in infected macrophages. STAT6 was activated in infected macrophages exposed to either FGF-2 or IGF-1, and STAT6 was critical to the FGFR-1- and IGF-1R-mediated expression of arg1. The converse was also true as inhibition of FGFR-1 and IGF-1R reduced the activation of STAT6 in infected macrophages. Collectively, these data indicate that the FGFR/IGF-1R and IL-4 signaling pathways converge at STAT6 to promote pathologic arg1 expression and intracellular parasite survival in VL. Targeted interruption of these pathological processes offers an approach to restrain this relentlessly progressive disease.
authors: Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas, United States of America; Laboratório Interdisciplinar de Pesquisas Médicas (LIPMED), Instituto Oswaldo Cruz-FIOCRUZ, Rio de Janeiro, Brazil.
authors: E Yaneth
authors: EY
authors: Osorio
authors: Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas, United States of America; Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, United States of America.
authors: Bruno L
authors: BL
authors: Travi
authors: Laboratório Interdisciplinar de Pesquisas Médicas (LIPMED), Instituto Oswaldo Cruz-FIOCRUZ, Rio de Janeiro, Brazil.
authors: Alda M
authors: AM
authors: da Cruz
authors: Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas, United States of America.
authors: Omar A
authors: OA
authors: Saldarriaga
authors: Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, United States of America.
authors: Audrie A
authors: AA
authors: Medina
authors: Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas, United States of America; Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, United States of America; Center for Tropical Diseases, and Institute for Human Infection and Immunity, University of Texas Medical Branch, Galveston, Texas, United States of America; Department of Pathology, and Sealy Center for Vaccine Development, University of Texas Medical Branch, Galveston, Texas, United States of America.
authors: Peter C
authors: PC
authors: Melby
mesh_terms: D000818:Animals; D001119:Arginase / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002478:Cells, Cultured; D018450:Disease Progression; D004790:Enzyme Induction / Q000187:drug effects; D006790:Host-Parasite Interactions / Q000187:drug effects; D015847:Interleukin-4 / Q000378:metabolism; D007893:Leishmania donovani / Q000254:growth & development / Q000276:immunology / Q000472:pathogenicity / Q000502:physiology; D007898:Leishmaniasis, Visceral / Q000276:immunology* / Q000378:metabolism / Q000469:parasitology / Q000503:physiopathology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000469:parasitology; D008647:Mesocricetus; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034622:RNA Interference; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D050800:STAT6 Transcription Factor / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism / Q000469:parasitology
chemical_list: D047428:Protein Kinase Inhibitors; D011994:Recombinant Proteins; D050800:STAT6 Transcription Factor; D015847:Interleukin-4; D051496:Receptor, Fibroblast Growth Factor, Type 1; D017526:Receptor, IGF Type 1; D001119:Arginase