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Related Concept Videos

NF-κB-dependent Signaling Pathway02:26

NF-κB-dependent Signaling Pathway

The transcription factor NF-κB was discovered in 1986 in the lab of Nobel laureate Professor David Baltimore, for its interaction with the immunoglobulin light chain enhancer in B-cells. After more than three decades of study, it is now evident that NF-κB regulates the expression of over 100 genes. Most of these genes play an essential role in the innate and adaptive immune responses as well as the inflammatory responses of animals.
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NF-kB-dependent Signaling Pathway02:26

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The transcription factor NF-κB was discovered in 1986 in the lab of Nobel laureate Professor David Baltimore, for its interaction with the immunoglobulin light chain enhancer in B-cells. After more than three decades of study, it is now evident that NF-κB regulates the expression of over 100 genes. Most of these genes play an essential role in the innate and adaptive immune responses as well as the inflammatory responses of animals.
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Several cytokine receptors have tightly bound Janus kinase or JAK proteins attached at their cytosolic tail. Small signaling molecules such as cytokines, growth hormones, or prolactins bind to the cytokine receptors and initiate their dimerization. The dimerization brings the cytosolic JAKs together that trans-phosphorylate and activates each other. The activated JAKs now phosphorylate cytosolic tails of the cytokine receptors, which serve as binding sites for adaptor proteins such as  SH2...
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Gene transcription is regulated by the synergistic action of several proteins that form a complex at a gene regulatory site. This is observed in eukaryotes, where the regulation of gene expression is a complex process. Regulatory proteins in eukaryotes can broadly be classified into two types – regulators that bind directly to specific DNA sequences and co-regulators that associate with regulatory proteins but cannot directly bind to the DNA. These co-regulators are further divided into...
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Multivesicular bodies (MVBs) are mature endosomes that sort ubiquitinated proteins and then fuse with lysosomes to degrade the sorted proteins. Epidermal growth factor (EGF) and its receptor (EGFR) form a complex that can be internalized through endocytosis, sorted into an MVB, and later degraded.
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B Cell Activation and Differentiation

The adaptive immune response, a sophisticated defense mechanism, relies on the activation and differentiation of B lymphocytes, or B cells. These processes enable our bodies to mount a tailored response against specific pathogens such as bacteria, free virus particles, toxins, and parasites.
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NF-{kappa}B is required for STAT-4 expression during dendritic cell maturation.

Maria Elena Remoli1, Josiane Ragimbeau, Elena Giacomini

  • 1Department of Infectious, Parasitic and Immune-Mediated Diseases, Istituto Superiore di Sanità, 00161 Rome, Italy.

Journal of Leukocyte Biology
|October 19, 2006
PubMed
Summary

Signal transducer and activator of transcription 4 (STAT-4) is regulated by NF-kappaB during dendritic cell maturation. This regulation primes dendritic cells for cytokine signaling in lymphoid organs.

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Area of Science:

  • Immunology
  • Cell Biology
  • Molecular Biology

Background:

  • Signal transducer and activator of transcription 4 (STAT-4) is crucial for T helper 1 (Th1) cell differentiation.
  • STAT-4 expression extends beyond lymphoid cells to myeloid cells like monocytes, macrophages, and dendritic cells (DCs).
  • Understanding STAT-4 regulation in DCs is key to immune response modulation.

Purpose of the Study:

  • To investigate STAT-4 expression and regulation in human monocyte-derived dendritic cells (moDCs).
  • To identify the molecular mechanisms controlling STAT-4 gene expression during DC maturation.
  • To elucidate the role of STAT-4 in preparing DCs for the cytokine milieu of lymphoid organs.

Main Methods:

  • Induction of STAT-4 expression by various stimuli including Toll-like receptor (TLR) ligands, pathogens, CD40 ligand, and pro-inflammatory cytokines.
  • Analysis of STAT-4 tyrosine phosphorylation in response to type I interferon (IFN) and interleukin-12 (IL-12).
  • Cloning and functional analysis of the STAT-4 promoter, including electrophoretic mobility shift assays (EMSAs) and chromatin immunoprecipitation (ChIP) to identify transcription factor binding sites and involved proteins (NF-kappaB/Rel dimers).

Main Results:

  • STAT-4 expression in human moDCs is induced by multiple stimuli, including TLR ligands, pathogens, CD40L, TNF-alpha, and IL-1beta.
  • STAT-4 is tyrosine-phosphorylated in mature human DCs upon stimulation with type I IFN, but not IL-12.
  • A specific NF-kappaB binding site (-969/-959 bp) in the STAT-4 promoter is critical for its gene expression in primary human DCs, with p65/p50 and p50/p50 NF-kappaB dimers being the primary regulators.

Conclusions:

  • STAT-4 expression in dendritic cells is tightly regulated by NF-kappaB activation during DC maturation.
  • This NF-kappaB-mediated regulation of STAT-4 is essential for DC function and their responsiveness to cytokine signals.
  • The findings highlight a mechanism by which DCs are prepared to interact with the immune environment in lymphoid organs.