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.
Division of Infectious Diseases, University of California, and Loewenstein Laboratory for Tuberculosis Research, San Francisco General Hospital, San Francisco, CA 94110, USA.
Vijaya
V
Nagabhushanam
Alejandra
A
Solache
Li-Min
LM
Ting
Claire J
CJ
Escaron
Jennifer Y
JY
Zhang
Joel D
JD
Ernst
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