Inflammasome-Mediated IL-1β Production in Humans with Cystic Fibrosis

Abstract

BackgroundInflammation and infection are major determinants of disease severity and consequently, the quality of life and outcome for patients with cystic fibrosis (CF). Interleukin-1 beta (IL-1β) is a key inflammatory mediator. Secretion of biologically active IL-1β involves inflammasome-mediated processing. Little is known about the contribution of IL-1β and the inflammasomes in CF inflammatory disease. This study examines inflammasome-mediated IL-1β production in CF bronchial epithelial cell lines and human patients with CF.ResultsBronchial epithelial cell lines were found to produce negligible amounts of basal or stimulated IL-1β compared to hematopoeitic cells and they did not significantly upregulate caspase-1 activity upon inflammasome stimulation. In contrast, peripheral blood mononuclear cells (PBMCs) from both CF and healthy control subjects produced large amounts of IL-1β and strongly upregulated caspase-1 activity upon inflammasome stimulation. PBMCs from CF patients and controls displayed similar levels of caspase-1 activation and IL-1β production when stimulated with inflammasome activators. This IL-1β production was dependent on NF-κB activity and could be enhanced by priming with LPS. Finally, chemical inhibition of CFTR activity in control PBMCs and THP-1 cells did not significantly alter IL-1β or IL-8 production in response to P. aeruginosa.ConclusionHematopoeitic cells appear to be the predominant source of inflammasome-induced pro-inflammatory IL-1β in CF. PBMCs derived from CF subjects display preserved inflammasome activation and IL-1β secretion in response to the major CF pathogen Pseudomonas aeruginosa. However, our data do not support the hypothesis that increased IL-1β production in CF subjects is due to an intrinsic increase in NF-κB activity through loss of CFTR function.

Bile Acids Repress Hypoxia-Inducible Factor 1 Signaling and Modulate the Airway Immune Response

“…Additionally, our results show that CDCA did not affect P. aeruginosa growth. PAO1 LPS was specifically found to be involved in the modulation of HIF-1␣ by BAs in our model, while heat-killed PAO1 also induced both IL-6 and IL-8, consistent with the findings presented in previous reports (55,56). However, this does not rule out the involvement of bacterial secreted factors in BA-mediated suppression of HIF-1␣ and modulation of the immune response.…”

Modulators affecting the immune dialogue between human immune and colon cancer cells

“…Endogenous type interferon 1 (IFN-1) released by colon mononuclear cells in mice with T-cell colitis has been demonstrated to be essential for stimulated production of the anti-inflammatory cytokines IL-10, IL-1ra and IL-27 [21] . Inflammasomes are closely related to chronic inflammation since they act as activators of IL-1β and IL-18 release by PBMC [22,23] . Moreover, activation of inflammasomes may stimulate cancer development [24] .…”

Staphylococcus aureus Survives in Cystic Fibrosis Macrophages, Forming a Reservoir for Chronic Pneumonia

“…Macrophages from CF patients and mice have a dysfunction in inflammatory cytokine production, in particular the production of gamma interferon (IFN-␥), interleukin-1␣␤ (IL-1␣␤), IL-6, IL-8/KC, and tumor necrosis factor alpha (TNF-␣), and impaired killing of pathogens (20)(21)(22)(23)(24)(25)(26)(27). Lysosomal functions of macrophages lacking Cftr might also be compromised, although conflicting data have been published on this issue.…”