title: Leishmania donovani-induced expression of suppressor of cytokine signaling 3 in human macrophages: a novel mechanism for intracellular parasite suppression of activation.
abstract: Leishmania donovani protozoan parasites, the causative agent of visceral leishmaniasis, establish an infection partly by interfering with cytokine signaling in the host macrophages. Therefore, we investigated the expression of the suppressor of cytokine signaling (SOCS) genes in human macrophages infected with L. donovani. The expression of SOCS3 mRNA was induced transiently after exposure to live or heat-killed parasites, but not purified lipophosphoglycan, while that of other SOCS genes remained unchanged. SOCS3 gene expression was not dependent on phagocytosis or on cytokines released by L. donovani-infected macrophages, such as interleukin-1beta or tumor necrosis factor alpha. In addition, Leishmania used a different signaling pathway(s) than bacterial lipopolysaccharide to induce SOCS3 mRNA, as indicated by the kinetics of induction and sensitivity to polymyxin B inhibition. Finally, phosphorylation of the STAT1 transcription factor was significantly reduced in L. donovani-infected macrophages and required de novo transcription. The induction of SOCS3 provides a potent inhibitory mechanism by which intracellular microorganisms may suppress macrophage activation and interfere with the host immune response.
authors.affiliation: Division of Bacterial, Parasitic, and Allergenic Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892, USA.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Bertholet
authors.forename: Harold L
authors.initials: HL
authors.lastname: Dickensheets
authors.forename: Faruk
authors.initials: F
authors.lastname: Sheikh
authors.forename: Albert A
authors.initials: AA
authors.lastname: Gam
authors.forename: Raymond P
authors.initials: RP
authors.lastname: Donnelly
authors.forename: Richard T
authors.initials: RT
authors.lastname: Kenney
mesh_terms: D000818:Animals; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D007893:Leishmania donovani / Q000472:pathogenicity*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008262:Macrophage Activation; D008264:Macrophages / Q000187:drug effects / Q000469:parasitology*; D009000:Monocytes / Q000187:drug effects / Q000469:parasitology; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins; D015398:Signal Transduction; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014157:Transcription Factors
chemical_list: D016207:Cytokines; D008070:Lipopolysaccharides; D011506:Proteins; D012333:RNA, Messenger; D012097:Repressor Proteins; C106644:SOCS3 protein, human; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014157:Transcription Factors; D007371:Interferon-gamma