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IFN- Secreted during Infection Is Necessary but Not Sufficient for Negative Feedback Regulation of IFN- Signaling by Mycobacterium tuberculosis¹

Savita Prabhakar^*, Yaming Qiao^*, Antony Canova^*, Doris B. Tse and Richard Pine^2,*

^* Public Health Research Institute, Newark, NJ 07103; and Division of Infectious Disease and Immunology, Department of Medicine, New York University School of Medicine, New York, NY 10016

IFN- 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- secretion and down-regulation of IFN- signaling in human APC and the human monocytic cell line THP-1, which provides a model for these studies. Neutralization of secreted IFN- prevents inhibition of IFN- signaling during infection, but several lines of evidence distinguish inhibition due to infection from a negative feedback response to only IFN-. First, greater inhibition of IFN--stimulated STAT-1 tyrosine phosphorylation occurs 3 days postinfection than 1 or 3 days after IFN- pretreatment. Second, LPS also induces IFN- secretion and causes IFN--dependent down-regulation of IFN- signaling, yet the inhibition differs from that caused by infection. Third, IFN- 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- 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- 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- 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- signaling by M. tuberculosis occurs together with a previously undescribed combination of inhibitory intracellular events.

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