PMID- 24967908 OWN - NLM STAT- MEDLINE DCOM- 20150813 LR - 20211021 IS - 1553-7374 (Electronic) IS - 1553-7366 (Print) IS - 1553-7366 (Linking) VI - 10 IP - 6 DP - 2014 Jun TI - Growth factor and Th2 cytokine signaling pathways converge at STAT6 to promote arginase expression in progressive experimental visceral leishmaniasis. PG - e1004165 LID - 10.1371/journal.ppat.1004165 [doi] LID - e1004165 AB - 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. FAU - Osorio, E Yaneth AU - Osorio EY AD - Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas, United States of America; Laboratorio Interdisciplinar de Pesquisas Medicas (LIPMED), Instituto Oswaldo Cruz-FIOCRUZ, Rio de Janeiro, Brazil. FAU - Travi, Bruno L AU - Travi BL AD - 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. FAU - da Cruz, Alda M AU - da Cruz AM AD - Laboratorio Interdisciplinar de Pesquisas Medicas (LIPMED), Instituto Oswaldo Cruz-FIOCRUZ, Rio de Janeiro, Brazil. FAU - Saldarriaga, Omar A AU - Saldarriaga OA AD - Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas, United States of America. FAU - Medina, Audrie A AU - Medina AA AD - Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, United States of America. FAU - Melby, Peter C AU - Melby PC AD - 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. LA - eng GR - R01 AI061624/AI/NIAID NIH HHS/United States PT - Journal Article DEP - 20140626 PL - United States TA - PLoS Pathog JT - PLoS pathogens JID - 101238921 RN - 0 (Protein Kinase Inhibitors) RN - 0 (Recombinant Proteins) RN - 0 (STAT6 Transcription Factor) RN - 207137-56-2 (Interleukin-4) RN - EC 2.7.10.1 (Receptor, Fibroblast Growth Factor, Type 1) RN - EC 2.7.10.1 (Receptor, IGF Type 1) RN - EC 3.5.3.1 (Arginase) SB - IM MH - Animals MH - Arginase/genetics/*metabolism MH - Cell Line MH - Cells, Cultured MH - Disease Progression MH - Enzyme Induction/drug effects MH - Host-Parasite Interactions/drug effects MH - Interleukin-4/metabolism MH - Leishmania donovani/growth & development/immunology/pathogenicity/physiology MH - Leishmaniasis, Visceral/*immunology/metabolism/parasitology/physiopathology MH - Macrophages/drug effects/immunology/metabolism/parasitology MH - Mesocricetus MH - Protein Kinase Inhibitors/pharmacology MH - RNA Interference MH - Receptor, Fibroblast Growth Factor, Type 1/*agonists/antagonists & inhibitors/genetics/metabolism MH - Receptor, IGF Type 1/*agonists/antagonists & inhibitors/genetics/metabolism MH - Recombinant Proteins/chemistry/metabolism MH - STAT6 Transcription Factor/agonists/antagonists & inhibitors/genetics/*metabolism MH - *Signal Transduction/drug effects MH - Th2 Cells/drug effects/*immunology/metabolism/parasitology PMC - PMC4072777 COIS- The authors have declared that no competing interests exist. EDAT- 2014/06/27 06:00 MHDA- 2015/08/14 06:00 PMCR- 2014/06/26 CRDT- 2014/06/27 06:00 PHST- 2013/09/17 00:00 [received] PHST- 2014/04/21 00:00 [accepted] PHST- 2014/06/27 06:00 [entrez] PHST- 2014/06/27 06:00 [pubmed] PHST- 2015/08/14 06:00 [medline] PHST- 2014/06/26 00:00 [pmc-release] AID - PPATHOGENS-D-13-02456 [pii] AID - 10.1371/journal.ppat.1004165 [doi] PST - epublish SO - PLoS Pathog. 2014 Jun 26;10(6):e1004165. doi: 10.1371/journal.ppat.1004165. eCollection 2014 Jun.