title: IFN-alpha beta secreted during infection is necessary but not sufficient for negative feedback regulation of IFN-alpha beta signaling by Mycobacterium tuberculosis.
abstract: IFN-alphabeta functions in the transition from innate to adaptive immunity and may impinge on the interaction of Mycobacterium tuberculosis with its host. Infection by M. tuberculosis causes IFN-alphabeta secretion and down-regulation of IFN-alphabeta signaling in human APC and the human monocytic cell line THP-1, which provides a model for these studies. Neutralization of secreted IFN-alphabeta prevents inhibition of IFN-alpha signaling during infection, but several lines of evidence distinguish inhibition due to infection from a negative feedback response to only IFN-alphabeta. First, greater inhibition of IFN-alpha-stimulated STAT-1 tyrosine phosphorylation occurs 3 days postinfection than 1 or 3 days after IFN-alphabeta pretreatment. Second, LPS also induces IFN-alphabeta secretion and causes IFN-alphabeta-dependent down-regulation of IFN-alpha signaling, yet the inhibition differs from that caused by infection. Third, IFN-alpha signaling is inhibited when cells are grown in conditioned medium collected from infected cells 1 day postinfection, but not if it is collected 3 days postinfection. Because IFN-alphabeta is stable, the results with conditioned medium suggest the involvement of an additional, labile substance during infection. Further characterizing signaling for effects of infection, we found that cell surface IFN-alphabeta receptor is not reduced by infection, but that infection increases association of protein tyrosine phosphatase 1c with the receptor and with tyrosine kinase 2. Concomitantly, IFN-alpha stimulation of tyrosine kinase 2 tyrosine phosphorylation and kinase activity decreases in infected cells. Moreover, infection reduces the abundance of JAK-1 and tyrosine-phosphorylated JAK-1. Thus, the distinctive down-regulation of IFN-alpha signaling by M. tuberculosis occurs together with a previously undescribed combination of inhibitory intracellular events.
authors.affiliation: Public Health Research Institute, Newark, NJ 07103, USA.
authors.forename: Savita
authors.initials: S
authors.lastname: Prabhakar
authors.forename: Yaming
authors.initials: Y
authors.lastname: Qiao
authors.forename: Antony
authors.initials: A
authors.lastname: Canova
authors.forename: Doris B
authors.initials: DB
authors.lastname: Tse
authors.forename: Richard
authors.initials: R
authors.lastname: Pine
mesh_terms: D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D017077:Culture Media, Conditioned / Q000494:pharmacology; D003593:Cytoplasm / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D015536:Down-Regulation / Q000276:immunology*; D005246:Feedback; D006801:Humans; D016898:Interferon-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology; D016899:Interferon-beta / Q000378:metabolism* / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins; D053613:Janus Kinase 1; D008070:Lipopolysaccharides / Q000494:pharmacology; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D010766:Phosphorylation; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D053633:Receptor, Interferon alpha-beta; D017471:Receptors, Interferon / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D053634:TYK2 Kinase; D014443:Tyrosine / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D017077:Culture Media, Conditioned; D016898:Interferon-alpha; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; D017471:Receptors, Interferon; D053633:Receptor, Interferon alpha-beta; D014443:Tyrosine; D016899:Interferon-beta; D011505:Protein-Tyrosine Kinases; C507904:JAK1 protein, human; D053613:Janus Kinase 1; D053634:TYK2 Kinase; C070139:TYK2 protein, human; C509249:PTPN6 protein, human; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases