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Allele-specific induction of IL-1β expression by C/EBPβ and PU.1 contributes to increased tuberculosis susceptibility.

Zhang G, Zhou B, Li S, Yue J, Yang H, Wen Y, Zhan S, Wang W, Liao M, Zhang M, Zeng G, Feng CG, Sassetti CM, Chen X - PLoS Pathog. (2014)

Bottom Line: Mycobacterium tuberculosis infection is associated with a spectrum of clinical outcomes, from long-term latent infection to different manifestations of progressive disease.Thus, the ultimate contribution of individual inflammatory pathways to the outcome of M. tuberculosis infection remains ambiguous.In this study, we identified a naturally-occurring polymorphism in the human IL1B promoter region, which alters the association of the C/EBPβ and PU.1 transcription factors and controls Mtb-induced IL-1β production.

View Article: PubMed Central - PubMed

Affiliation: Guangdong Key Lab of Emerging Infectious Diseases, Guangdong Medical College, Shenzhen, China; Shenzhen Key Lab of Infection and Immunity, Shenzhen Third People's Hospital, Guangdong Medical College, Shenzhen, China.

ABSTRACT
Mycobacterium tuberculosis infection is associated with a spectrum of clinical outcomes, from long-term latent infection to different manifestations of progressive disease. Pro-inflammatory pathways, such as those controlled by IL-1β, have the contrasting potential both to prevent disease by restricting bacterial replication, and to promote disease by inflicting tissue damage. Thus, the ultimate contribution of individual inflammatory pathways to the outcome of M. tuberculosis infection remains ambiguous. In this study, we identified a naturally-occurring polymorphism in the human IL1B promoter region, which alters the association of the C/EBPβ and PU.1 transcription factors and controls Mtb-induced IL-1β production. The high-IL-1β expressing genotype was associated with the development of active tuberculosis, the severity of pulmonary disease and poor treatment outcome in TB patients. Higher IL-1β expression did not suppress the activity of IFN-γ-producing T cells, but instead correlated with neutrophil accumulation in the lung. These observations support a specific role for IL-1β and granulocytic inflammation as a driver of TB disease progression in humans, and suggest novel strategies for the prevention and treatment of tuberculosis.

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C/EBPB and PU.1 expression induced by Mtb temporally correlates with IL1B expression.(A-D) SYBR Green-based real-time qPCR assay for the gene expression of IL1B (A), C/EBPB (B), PU.1 (C), and TBP (D) by differentiated U937 cells in response to Mtb lysate (20 µg/mL) or H37Ra infection (MOI = 10). The data are expressed as mRNA copy number relative to the house keeping gene GAPDH. Differences between groups were compared with the ANOVA/Newman-Keuls multiple comparison test. (E-G) Correlation analysis between the C/EBPB (E), PU.1 (F), or TBP (G) expression and IL1B expression. The coefficient r and P values are indicated. (H-K) Dynamic change of IL1B (H), C/EBPB (I), PU.1 (J) and TBP (K) expression by differentiated U937 upon stimulation with Mtb lysate (20 µg/mL). *, p<0.05; **, p<0.01.
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ppat-1004426-g005: C/EBPB and PU.1 expression induced by Mtb temporally correlates with IL1B expression.(A-D) SYBR Green-based real-time qPCR assay for the gene expression of IL1B (A), C/EBPB (B), PU.1 (C), and TBP (D) by differentiated U937 cells in response to Mtb lysate (20 µg/mL) or H37Ra infection (MOI = 10). The data are expressed as mRNA copy number relative to the house keeping gene GAPDH. Differences between groups were compared with the ANOVA/Newman-Keuls multiple comparison test. (E-G) Correlation analysis between the C/EBPB (E), PU.1 (F), or TBP (G) expression and IL1B expression. The coefficient r and P values are indicated. (H-K) Dynamic change of IL1B (H), C/EBPB (I), PU.1 (J) and TBP (K) expression by differentiated U937 upon stimulation with Mtb lysate (20 µg/mL). *, p<0.05; **, p<0.01.

Mentions: To determine if C/EBPβ and PU.1 are produced in a manner that is consistent with the proposed role in IL-1β regulation, we quantified the expression of all three genes in the monocyte-like U937 cells after stimulation with heat killed Mtb or infection with the live attenuated strain of Mtb, H37Ra. Consistent with previous reports, both stimuli induced IL1B mRNA expression (Fig. 5A). More importantly, we found Mtb exposure also induced the expression of C/EBPB (Fig. 5B) and PU.1 (Fig. 5C), but no significant difference was observed in TBP expression (Fig. 5D). Furthermore, the mRNA level of IL1B was significantly correlated with that of both C/EBPB (r = 0.887, P<0.0001, Fig. 5E) and PU.1 (r = 0.811, P = 0.0001, Fig. 5F), and not correlated with TBP expression (r = 0.314, P = 0.236, Fig. 5G). The induction of PU.1 and C/EBPB mRNA expression occurred earlier after stimulation than IL1B (Fig. 5H-K), which is consistent with a role for PU.1 and C/EBPβ in regulating the IL1B promoter in response to Mtb infection.


Allele-specific induction of IL-1β expression by C/EBPβ and PU.1 contributes to increased tuberculosis susceptibility.

Zhang G, Zhou B, Li S, Yue J, Yang H, Wen Y, Zhan S, Wang W, Liao M, Zhang M, Zeng G, Feng CG, Sassetti CM, Chen X - PLoS Pathog. (2014)

C/EBPB and PU.1 expression induced by Mtb temporally correlates with IL1B expression.(A-D) SYBR Green-based real-time qPCR assay for the gene expression of IL1B (A), C/EBPB (B), PU.1 (C), and TBP (D) by differentiated U937 cells in response to Mtb lysate (20 µg/mL) or H37Ra infection (MOI = 10). The data are expressed as mRNA copy number relative to the house keeping gene GAPDH. Differences between groups were compared with the ANOVA/Newman-Keuls multiple comparison test. (E-G) Correlation analysis between the C/EBPB (E), PU.1 (F), or TBP (G) expression and IL1B expression. The coefficient r and P values are indicated. (H-K) Dynamic change of IL1B (H), C/EBPB (I), PU.1 (J) and TBP (K) expression by differentiated U937 upon stimulation with Mtb lysate (20 µg/mL). *, p<0.05; **, p<0.01.
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ppat-1004426-g005: C/EBPB and PU.1 expression induced by Mtb temporally correlates with IL1B expression.(A-D) SYBR Green-based real-time qPCR assay for the gene expression of IL1B (A), C/EBPB (B), PU.1 (C), and TBP (D) by differentiated U937 cells in response to Mtb lysate (20 µg/mL) or H37Ra infection (MOI = 10). The data are expressed as mRNA copy number relative to the house keeping gene GAPDH. Differences between groups were compared with the ANOVA/Newman-Keuls multiple comparison test. (E-G) Correlation analysis between the C/EBPB (E), PU.1 (F), or TBP (G) expression and IL1B expression. The coefficient r and P values are indicated. (H-K) Dynamic change of IL1B (H), C/EBPB (I), PU.1 (J) and TBP (K) expression by differentiated U937 upon stimulation with Mtb lysate (20 µg/mL). *, p<0.05; **, p<0.01.
Mentions: To determine if C/EBPβ and PU.1 are produced in a manner that is consistent with the proposed role in IL-1β regulation, we quantified the expression of all three genes in the monocyte-like U937 cells after stimulation with heat killed Mtb or infection with the live attenuated strain of Mtb, H37Ra. Consistent with previous reports, both stimuli induced IL1B mRNA expression (Fig. 5A). More importantly, we found Mtb exposure also induced the expression of C/EBPB (Fig. 5B) and PU.1 (Fig. 5C), but no significant difference was observed in TBP expression (Fig. 5D). Furthermore, the mRNA level of IL1B was significantly correlated with that of both C/EBPB (r = 0.887, P<0.0001, Fig. 5E) and PU.1 (r = 0.811, P = 0.0001, Fig. 5F), and not correlated with TBP expression (r = 0.314, P = 0.236, Fig. 5G). The induction of PU.1 and C/EBPB mRNA expression occurred earlier after stimulation than IL1B (Fig. 5H-K), which is consistent with a role for PU.1 and C/EBPβ in regulating the IL1B promoter in response to Mtb infection.

Bottom Line: Mycobacterium tuberculosis infection is associated with a spectrum of clinical outcomes, from long-term latent infection to different manifestations of progressive disease.Thus, the ultimate contribution of individual inflammatory pathways to the outcome of M. tuberculosis infection remains ambiguous.In this study, we identified a naturally-occurring polymorphism in the human IL1B promoter region, which alters the association of the C/EBPβ and PU.1 transcription factors and controls Mtb-induced IL-1β production.

View Article: PubMed Central - PubMed

Affiliation: Guangdong Key Lab of Emerging Infectious Diseases, Guangdong Medical College, Shenzhen, China; Shenzhen Key Lab of Infection and Immunity, Shenzhen Third People's Hospital, Guangdong Medical College, Shenzhen, China.

ABSTRACT
Mycobacterium tuberculosis infection is associated with a spectrum of clinical outcomes, from long-term latent infection to different manifestations of progressive disease. Pro-inflammatory pathways, such as those controlled by IL-1β, have the contrasting potential both to prevent disease by restricting bacterial replication, and to promote disease by inflicting tissue damage. Thus, the ultimate contribution of individual inflammatory pathways to the outcome of M. tuberculosis infection remains ambiguous. In this study, we identified a naturally-occurring polymorphism in the human IL1B promoter region, which alters the association of the C/EBPβ and PU.1 transcription factors and controls Mtb-induced IL-1β production. The high-IL-1β expressing genotype was associated with the development of active tuberculosis, the severity of pulmonary disease and poor treatment outcome in TB patients. Higher IL-1β expression did not suppress the activity of IFN-γ-producing T cells, but instead correlated with neutrophil accumulation in the lung. These observations support a specific role for IL-1β and granulocytic inflammation as a driver of TB disease progression in humans, and suggest novel strategies for the prevention and treatment of tuberculosis.

Show MeSH
Related in: MedlinePlus