Dataset Information

I?B? Regulates Human Monocyte Pro-Inflammatory Responses Induced by Streptococcus pneumoniae.

ABSTRACT: Pneumococcal lung infections represent a major cause of death worldwide. Single nucleotide polymorphisms (SNPs) in the NFKBIZ gene, encoding the transcription factor I?B?, are associated with increased susceptibility to invasive pneumococcal disease. We hence analyzed how I?B? might regulate inflammatory responses to pneumococcal infection. We first demonstrate that I?B? is expressed in human blood monocytes but not in bronchial epithelial cells, in response to wild type pneumococcal strain D39. D39 transiently induced I?B? in a dose dependent manner, with subsequent induction of downstream molecules involved in host defense. Of these molecules, I?B? knockdown reduced the expression of IL-6 and GMCSF. Furthermore, I?B? overexpression increased the activity of IL-6 and GMCSF promoters, supporting the knockdown findings. Pneumococci lacking either pneumolysin or capsule still induced I?B?. While inhibition of TLR1/TLR2 blocked D39 induced I?B? expression, TLR4 inhibition did not. Blockade of p38 MAP kinase and NF?B suppressed D39 induced I?B?. Overall, our data demonstrates that I?B? regulates monocyte inflammatory responses to Streptococcus pneumoniae by promoting the production of IL-6 and GMCSF.

SUBMITTER: Sundaram K

PROVIDER: S-EPMC5012667 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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IκBζ Regulates Human Monocyte Pro-Inflammatory Responses Induced by Streptococcus pneumoniae.

Sundaram Kruthika K Rahman Mohd Akhlakur MA Mitra Srabani S Knoell Daren L DL Woodiga Shireen A SA King Samantha J SJ Wewers Mark D MD

PloS one 20160906 9

Pneumococcal lung infections represent a major cause of death worldwide. Single nucleotide polymorphisms (SNPs) in the NFKBIZ gene, encoding the transcription factor IκBζ, are associated with increased susceptibility to invasive pneumococcal disease. We hence analyzed how IκBζ might regulate inflammatory responses to pneumococcal infection. We first demonstrate that IκBζ is expressed in human blood monocytes but not in bronchial epithelial cells, in response to wild type pneumococcal strain D39. ...[more]

PMID: 27597997

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Project description:Previous studies have revealed that activation of the Toll‑like receptor 4 (TLR4)‑mediated proinflammatory signaling pathway plays an important role in acute inflammation, sepsis and chronic inflammatory disorders. Moreover, TLR4 significantly contributes to lipopolysaccharide (LPS)‑induced immune response. Thus, modulation of the TLR4 pathway is an important strategy to specifically target these pathologies. The aim of the present study was to develop a complete human anti‑TLR4 IgG2 antibody by screening human TLR4 Fab from a phage‑display library and integrating it with constant regions of the heavy chain of human IgG2 via antibody engineering. ELISA, a BLItz system and fluorescence‑activated cell sorting were used to assess its affinity. Furthermore, mouse‑derived peritoneal macrophages were treated with human anti‑TLR4 IgG2 and induced with LPS in vitro. Reverse transcription‑quantitative PCR and western blotting were used to determine mRNA expression levels of cytokines and phosphorylation levels of signaling pathways, respectively. It was found that human anti‑TLR4 IgG2 bound to TLR4 with a high affinity of 8.713x10‑10 M, and that preincubation with anti‑TLR4 IgG2 inhibited the LPS‑induced production of tumor necrosis factor‑α, interferon‑β and interleukin‑6 mRNA expression levels in mouse peritoneal macrophages. It was also demonstrated that human anti‑TLR4 IgG2 inhibited LPS‑induced TLR4 signaling by reducing the phosphorylation of the NF‑κB, mitogen‑activated protein kinase and interferon regulatory factor 3 signaling pathways. In addition, human anti‑TLR4 IgG2 protected mice from LPS challenge with a survival rate of 40% and also significantly increased the survival time in the cecal ligation and puncture model. Therefore, it was speculated that human anti‑TLR4 IgG2 plays a protective role against sepsis‑associated injury and is potentially applicable for the treatment of infection‑associated immune dysfunction.

Dataset Information

I?B? Regulates Human Monocyte Pro-Inflammatory Responses Induced by Streptococcus pneumoniae.

Publications

IκBζ Regulates Human Monocyte Pro-Inflammatory Responses Induced by Streptococcus pneumoniae.

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