Innate inhibition of adaptive immunity: Mycobacterium tuberculosis-induced IL-6 inhibits macrophage responses to IFN-gamma.
In humans and in mice, control of the intracellular pathogen, Mycobacterium tuberculosis (Mtb), requires IFN-gamma. Although the adaptive immune response results in production of substantial amounts of IFN-gamma in response to Mtb, the immune response is unable to eradicate the infection in most cases. We have previously reported evidence that Mtb inhibits macrophage responses to IFN-gamma, suggesting that this may limit the ability of IFN-gamma to stimulate macrophages to kill Mtb. We have also observed that uninfected macrophages, adjacent to infected macrophages in culture, exhibit decreased responses to IFN-gamma. Here we report that IL-6 secreted by Mtb-infected macrophages inhibits the responses of uninfected macrophages to IFN-gamma. IL-6 selectively inhibits a subset of IFN-gamma-responsive genes at the level of transcriptional activation without inhibiting activation or function of STAT1. Inhibition of macrophage responses to IFN-gamma by IL-6 requires new protein synthesis, but this effect is not attributable to suppressor of cytokine signaling 1 or 3. These results reveal a novel function for IL-6 and indicate that IL-6 secreted by Mtb-infected macrophages may contribute to the inability of the cellular immune response to eradicate infection.
Nagabhushanam
Vijaya
V
Division of Infectious Diseases, University of California, and Loewenstein Laboratory for Tuberculosis Research, San Francisco General Hospital, San Francisco, CA 94110, USA.
Solache
Alejandra
A
Ting
Li-Min
LM
Escaron
Claire J
CJ
Zhang
Jennifer Y
JY
Ernst
Joel D
JD
D000818:Animals; D002352:Carrier Proteins / Q000096:biosynthesis / Q000502:physiology; D002460:Cell Line; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000494:pharmacology; D015536:Down-Regulation / Q000276:immunology*; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D007111:Immunity, Cellular; D007113:Immunity, Innate; D007371:Interferon-gamma / Q000037:antagonists & inhibitors* / Q000502:physiology*; D015850:Interleukin-6 / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology*; D051379:Mice; D009169:Mycobacterium tuberculosis / Q000254:growth & development / Q000276:immunology*; D009687:Nuclear Proteins; D014176:Protein Biosynthesis / Q000276:immunology; D011506:Proteins / Q000502:physiology; D012097:Repressor Proteins; D000071222:Suppressor of Cytokine Signaling 1 Protein; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000235:genetics; D014157:Transcription Factors; D015533:Transcriptional Activation / Q000276:immunology
D002352:Carrier Proteins; D017077:Culture Media, Conditioned; D015850:Interleukin-6; D047908:Intracellular Signaling Peptides and Proteins; C083728:MHC class II transactivator protein; D009687:Nuclear Proteins; D011506:Proteins; D012097:Repressor Proteins; C108944:SOCS1 protein, human; C106644:SOCS3 protein, human; C491590:Socs1 protein, mouse; C491411:Socs3 protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D007371:Interferon-gamma