Gamma interferon activates human macrophages to become tumoricidal and leishmanicidal but enhances replication of macrophage-associated mycobacteria

Abstract

Recombinant human gamma interferon (rIFN-y) was examined for its ability to activate human peripheral blood monocyte-derived macrophages to kill tumor cells and to affect the replication of two phylogenetically distinct intracellular pathogens, Mycobacterium tuberculosis and Leishmania donovani. Macrophages preincubated overnight with doses of rIFN-y from 5 to 500 U/ml killed [3H]thymidine-labeled mouse L929 tumor targets, as measured by the release of [3H]thymidine into the supernatant after 48 h. Counts of macrophages initially infected with leishmania promastigotes showed that rIFN-y-pretreated macrophages could both inhibit the replication of and kill the resulting intramacrophage amastigotes over a 7-day period. However, rIFN-y pretreatment of macrophages actually enhanced mycobacterial replication over a 5-to 7-day period, as assessed by (i) counting acid-fast bacilli or (ii) lysing macrophages to release bacteria and determining the numbers of viable units. Mycobacterial growth was not affected by rIFN-y in the absence of macrophages. rIFN-y

Assessment ofin vitroimmunity toM ycobacterium tuberculosisin a human peripheral blood infection model using a luciferase reporter construct ofM. tuberculosisH37Rv

“…Although their effectiveness in blocking the relevant cytokines had not been tested directly, the lack of a significant effect of the neutralizing antibodies on the growth of M. tuberculosis confirms a previous finding using a model of M. tuberculosis-infected macrophages [16]. Previous studies performed by several groups to delineate the effect of cytokines on the growth of M. tuberculosis in human macrophages in vitro have shown controversial results [14][15][16]20,22]. Some of these studies have shown only weak inhibition [20,22], whereas others have shown enhancement [15,22] of the growth of virulent M. tuberculosis in human monocytes/macrophages activated with IFNγ.…”

“…Several cytokines have been suggested previously to have an inhibitory or enhancing effect on the growth of M. tuberculosis in human macrophages [15][16][17][18][19][20][21][22][23][24][25]. Among these, TNFα and IFN-γ have been studied extensively [15][16][17][18][19][20][21][22][23][24][25]. In the present work, to study the effect of TNF-α, IFN-γ, IL-12 and IL-10 on M. tuberculosis growth in whole blood cultures, we have used two approaches.…”

Hereditary hemochromatosis results in decreased iron acquisition and growth byMycobacterium tuberculosiswithin human macrophages

“…Although Fe is required for M.tb growth, it was not clear whether the decrease in Fe acquisition by M.tb located in HFE -MDM was sufficient to alter bacterial growth in the macrophage. In spite of decreasing access of M.tb to Fe, previous studies found that IFN-␥ treatment of human MDM does not inhibit the in vitro growth of M.tb [34,43]. Therefore, we compared growth of intracellular M.tb over time in MDM from hemochromatosis and healthy control subjects.…”

Specific Lymphoproliferation, Gamma Interferon Production, and Serum Immunoglobulin G Directed against a Purified 32 kDa Mycobacterial Protein Antigen (P32) in Patients with Active Tuberculosis

“…Whereas the antimycobacterial properties of murine peritoneal macrophages are strongly activated by natural and E. co//-derived IFN-y [14], the situation is less clear in man. Indeed, recent papers have demonstrated that human macrophages can become activated by gamma interferon in their tumoricidal and Leishmaniacidal properties, but that macrophage treatment with the lymphokine has weak, variable, or even enhancing effects on Myeobacterium tuberculosis replication [6,14].…”