Allele-Specific Induction of IL-1β Expression by C/EBPβ and PU.1 Contributes to Increased Tuberculosis Susceptibility

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.

PPAR-α Activation Mediates Innate Host Defense through Induction of TFEB and Lipid Catabolism

“…Indeed, proinflammatory responses are regarded as a double-edged sword between protective immunity and detrimental inflammatory pathogenesis during mycobacterial infection. Higher IL-1b expression correlated with an increased accumulation of neutrophils in the lung, suggesting a driving cytokine for granulocytic inflammation and TB disease progression (47). In addition, defective recruitment of anti-inflammatory dendritic cells and regulatory T cells resulted in the enhanced susceptibility to Mtb infection and excessive lung inflammation (48).…”

Interleukin-1 Beta—A Friend or Foe in Malignancies?

“…This included infectious diseases such as tuberculosis [44], neurodegenerative diseases such as Alzheimer’s disease [45], autoimmune and autoinflammatory diseases such as psoriasis [46] and diabetes type 2 [47], and the occurrence of tumors such as prostate cancer [48]. …”

Interactions between Type 1 Interferons and the Th17 Response in Tuberculosis: Lessons Learned from Autoimmune Diseases

“…However, this does not fully explain the harmful effects of T1-IFNs observed in TB. Most importantly, although IL-1β production is essential for protective immunity in the acute phase of disease in TB, it requires strict regulation as unchecked IL-1β signaling in TB can result in excessive PMN-mediated tissue damage (120, 123). Also, as explained in Box 2, IL-1β-mediated PGE 2 production is protective during acute disease but appears to have a detrimental effect during chronic disease.…”