Early Secreted Antigenic Target of 6-kDa of Mycobacterium tuberculosis Stimulates IL-6 Production by Macrophages through Activation of STAT3

Jung, Bock‐Gie; Wang, Xisheng; Yi, Na; Ma, Justin; Turner, Joanne; Samten, Buka

doi:10.1038/srep40984

Cited by 46 publications

(48 citation statements)

References 66 publications

(89 reference statements)

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“…Thus, we speculate that ESAT-6 may function as both priming and activation signals for IL-1β production in tuberculosis infection. As a priming signal, we showed that either incubation of macrophages or intranasal treatment of mouse with ESAT-6 induced pro-IL-1β expression, consistent with our previous reports that ESAT-6 stimulates macrophage production of inflammatory cytokine and chemokine (19, 38). As an activation signal, our data with MCC950, a novel selective NLRP3 inhibitor (23, 24), showed that Mtb stimulates mature IL-1β production by macrophages in an NLRP3 dependent manner, consistent with the previous study [16].…”

Section: Discussionsupporting

confidence: 91%

“…Mouse bone marrow-derived macrophages (BMDMs) were prepared as previously described with minor modifications (19).…”

Section: Methodsmentioning

confidence: 99%

“…Levels of pro-IL-1β, IL-1β and KC in the cell lysates and the culture supernatants were determined by western blot analysis using glyceraldehyde 3-phosphate dehydrogenase (GAPDH) as loading control with specific antibodies (Cell Signaling Technology) as previously described (19).…”

Section: Methodsmentioning

confidence: 99%

“…The expression of mRNA levels of IL-1β and SAA3 in BMDMs and lung homogenate cells was measured by Real-Time PCR from the total RNA using GAPDH as internal control with specific primer and probe sets (Applied Biosystems) as previously described (19).…”

Section: Methodsmentioning

confidence: 99%

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Mycobacterium tuberculosisstimulates IL-1β production by macrophages in an ESAT-6 dependent manner with the involvement of serum amyloid A3

Jung

Vankayalapati

Samten

2020

Preprint

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TX 75708-3154, phone 29 (903)-877-7665, fax (903) 877-5516, buka.samten@uthct.edu 30 4. Acknowledgment: We thank Dr. Charles A. Dinarello for his thoughtful guidance and 31 discussions.32 5. Brief summary: Mycobacterium tuberculosis stimulated the production of IL-1β by 33 macrophages and in mouse lungs with the activation of NLRP3 and K+ efflux in an ESAT-6 34 dependent manner with the involvement of SAA3. 35 36 37 38 39 40 41 42 43 44 45 46 3 ABSTRACT 47To explore interleukin (IL)-1β production in tuberculosis, we infected mouse bone marrow-derived 48 macrophages (BMDM) with Mycobacterium tuberculosis (Mtb) H37Rv, its early secreted antigenic target 49 protein of 6 kDa (ESAT-6) gene deletion (H37Rv:∆3875) or complemented strain (H37Rv:∆3875C) and 50 evaluated IL-1β production. H37Rv induced significantly increased IL-1β production by BMDMs 51 compared to non-infected BMDMs. In contrast, H37Rv:∆3875 induced significantly less mature IL-1β 52 production despite eliciting comparable levels of pro-IL-1β and IL-8 from BMDMs compared to H37Rv 53 and H37Rv:∆3875C. Blocking either NLRP3 or K + efflux diminished H37Rv-induced IL-1β production 54 by BMDMs. Infection of mice intranasally with H37Rv:∆3875 induced less IL-1β production in the lungs 55 compared with H37Rv.Intranasal delivery of ESAT-6 but not CFP10 induced production of IL-1β in 56 mouse lungs and RNA-Seq analysis identified serum amyloid A (SAA) 3 as one of the highly expressed 57 genes in mouse lungs. Infection of mice with H37Rv but not H37Rv:∆3875 induced expression of lung 58 SAA3 mRNA and protein, consistent with the effect of intranasal delivery of ESAT-6. Silencing SAA3 59 reduced Mtb-induced IL-1β production by BMDMs. We conclude that the production of SAA3 is required 60 for Mtb stimulated IL-1β production by macrophages in tuberculosis infection. 61 62 63 64 65 66 67 68 69 70Tuberculosis (TB) caused around 1.2 million deaths among HIV-negative people and an additional 71 251,000 deaths among HIV-positive people in 2018 (1), which is mainly due to the lack of a detailed 72 understanding of the molecular mechanisms of interactions between immune cells and the pathogen, 73 Mycobacterium tuberculosis (Mtb). Improved understanding of the host-pathogen interaction will lead to 74 an effective TB vaccine design and an identification of novel drug targets to improve clinical management 75 of drug-resistant TB infections. Macrophages play critical roles in tuberculosis infection as both host cells 76 providing intracellular niche for Mtb infection and growth and effector immune cells fighting against Mtb 77infection by communicating with other immune effector cells by producing different cytokines (2). 78Although IL-1β production by macrophages is pivotal for protection against TB infection (3, 4), several 79 clinical reports showed that IL-1β is also involved in TB pathogenesis. There is significantly increased 80 IL-1β mRNA in the alveolar macrophages and IL-1β protein in bronchoalveolar lavage fluid of TB 81 patients compared with healthy controls (5...

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Section: Discussionsupporting

confidence: 91%

“…Mouse bone marrow-derived macrophages (BMDMs) were prepared as previously described with minor modifications (19).…”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

Mycobacterium tuberculosisstimulates IL-1β production by macrophages in an ESAT-6 dependent manner with the involvement of serum amyloid A3

Jung

Vankayalapati

Samten

2020

Preprint

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“…In macrophages, ESAT-6-induced IL-6 or IL-10 expression have been identified as possible causes. 52,53 In addition to spontaneous IL-10 and IL-6 production, T-cells from tuberculosis patients were strongly activated in the presence of M. tuberculosis PPD to produce IL-10 and IL-6. These results suggested a dominant immunosuppressive T-cell phenotype in tuberculosis patients characterized by IL-10-positive M. tuberculosis-specific T-cells.…”

Section: Discussionmentioning

confidence: 99%

Constitutive STAT3 phosphorylation and IL-6/IL-10 co-expression are associated with impaired T-cell function in tuberculosis patients

et al. 2018

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T-cells critically contribute to protection against Mycobacterium tuberculosis infection, and impaired T-cell responses can lead to disease progression. Pro-inflammatory and immunosuppressive cytokines affect T-cells, and fine-tuned regulation of cytokine signaling via the Jak/STAT signaling pathways is crucial for appropriate T-cell function. Constitutive STAT3 phosphorylation as a consequence of aberrant cytokine signaling has been described to occur in pathognomonic T-cell responses in inflammatory and autoimmune diseases. We characterized blood samples from tuberculosis patients (n=28) and healthy contacts (n=28) from Ghana for M. tuberculosis-specific T-cell responses, constitutive cytokine production, and SOCS3 and pSTAT3 expression. Lentiviral modulation of primary CD4 T-cells was performed to determine the effects of SOCS3 on T-cell functions. T-cells from tuberculosis patients expressed higher levels of IL-10 and IL-6 and lower levels of T helper type (T)17 cytokines after M. tuberculosis-specific stimulation compared to healthy contacts. In addition, tuberculosis patients had higher IL-10 and IL-6 levels in the supernatants of non-stimulated immune cells and plasma samples compared to healthy contacts. Notably, aberrant cytokine expression was accompanied by high constitutive pSTAT3 levels and SOCS3 expression in T-cells. Multivariate analysis identified an IL-6/IL-10 co-expression-based principal component in tuberculosis patients that correlated with high pSTAT3 levels. SOCS3 contributed to a regulatory component, and tuberculosis patients with high SOCS3 expression showed decreased T1 cytokine expression and impaired IL-2-induced STAT5 phosphorylation. SOCS3 over-expression in primary CD4 T-cells confirmed the SOCS3 inhibitory function on IL-2-induced STAT5 phosphorylation. We conclude that constitutive pSTAT3 and high SOCS3 expression are influential factors that indicate impaired T-cell functions in tuberculosis patients.Cellular and Molecular Immunology advance online publication, 19 March 2018; doi:10.1038/cmi.2018.5.

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The potential impacts of early secreted antigenic target of 6 kDa of Mycobacterium tuberculosis on KSHV‐infected cells

Dai

Jung

Chen

et al. 2020

Journal of Medical Virology

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Kaposi's sarcoma‐associated herpesvirus (KSHV) causes several human cancers, including Kaposi's sarcoma (KS) and primary effusion lymphoma, which are mostly seen in immunocompromised patients, such as human immunodefeciency virus (HIV)+ individuals. Tuberculosis (TB), caused by the bacterial pathogen Mycobacterium tuberculosis (Mtb), remains one of the deadliest infectious diseases in the world. The risk of developing TB is dramatically higher in people living with HIV than among those without HIV infection. Case reports link cutaneous or pulmonary KS in HIV+ patients with mycobacterial co‐infections, however, impacts of Mtb infection or its products on KSHV‐infected cells are not known. We report here that ESAT‐6, a secreted Mtb virulence factor, induces viral reactivation from KSHV‐infected cells. KSHV‐infected pulmonary endothelial cells were resistant to ESAT‐6 induced inhibition of cell growth. Our data demonstrate that Mtb virulence factors influence the biology of KSHV‐infected cells, highlighting the need to study the interactions between these two pathogens commonly found in people living with HIV.

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Early Secreted Antigenic Target of 6-kDa of Mycobacterium tuberculosis Stimulates IL-6 Production by Macrophages through Activation of STAT3

Cited by 46 publications

References 66 publications

Mycobacterium tuberculosisstimulates IL-1β production by macrophages in an ESAT-6 dependent manner with the involvement of serum amyloid A3

Mycobacterium tuberculosisstimulates IL-1β production by macrophages in an ESAT-6 dependent manner with the involvement of serum amyloid A3

Constitutive STAT3 phosphorylation and IL-6/IL-10 co-expression are associated with impaired T-cell function in tuberculosis patients

The potential impacts of early secreted antigenic target of 6 kDa of Mycobacterium tuberculosis on KSHV‐infected cells

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