Biology and Signal Transduction pathways of the Lymphotoxin-αβ/LTβR system

in Cytokine & Growth Factor Reviews (2011), 22

This review focuses on the biological functions and signalling pathways activated by Lymphotoxin α (LTα)/Lymphotoxin β (LTβ) and their receptor LTβR. Genetic mouse models shed light on crucial roles for ... [more ▼]

This review focuses on the biological functions and signalling pathways activated by Lymphotoxin α (LTα)/Lymphotoxin β (LTβ) and their receptor LTβR. Genetic mouse models shed light on crucial roles for LT/LTβR to build and to maintain the architecture of lymphoid organs and to ensure an adapted immune response against invading pathogens. However, chronic inflammation, autoimmunity, cell death or cancer development are disorders that occur when the LT/LTβR system is twisted. Biological inhibitors, such as antagonist antibodies or decoy receptors, have been developed and used in clinical trials for diseases associated to the LT/LTβR system. Recent progress in the understanding of cellular trafficking and NF-κB signaling pathways downstream of LTα/LTβ may bring new opportunities to develop therapeutics that target the pathological functions of these cytokines. [less ▲]

TNFL–Induced p100 processing (TIPP) relies on the internalization of the cognate TNFR

Conference (2010, January)

Role of IKK and ERK pathways in intrinsic inflammation of cystic fibrosis airways

in Biochemical Pharmacology (2007), 73(12), 1982-1994

in cystic fibrosis (CF) patients, pulmonary inflammation is a major cause of morbidity and mortality and may precede bacterial colonization. The aim of the present study was to investigate the molecular ... [more ▼]

in cystic fibrosis (CF) patients, pulmonary inflammation is a major cause of morbidity and mortality and may precede bacterial colonization. The aim of the present study was to investigate the molecular mechanisms underlying intrinsic inflammation in cystic fibrosis air-ways. Using different cystic fibrosis cell models, we first demonstrated that, beside a high constitutive nuclear factor of kappaB (NF-kappa B) activity, CF cells showed a higher activator protein-1 (AP-1) activity as compared to their respective control cells. Gene expression profiles, confirmed by RT-PCR and ELISA, showed over-expression of numerous NF-KB and AP-1-dependent pro-inflammatory genes in CF cells in comparison with control cells. Activation of NF-KB was correlated with higher inhibitor of kappa B kinase (IKK) activity. In addition, Bio-plex phosphoprotein assays revealed higher extracellular signal-regulated kinase (ERK) phosphorylation in CFT-2 cells. Inhibition of this kinase strongly decreased expression of pro-inflammatory genes coding for growth-regulated proteins (Gro-alpha, Gro-beta and Gro-gamma) and interleukins (IL-1 beta, IL-6 and IL-8). Moreover, inhibition of secreted interleukin-1 beta (IL-1 beta) and basic fibroblast growth factor (bFGF) with neutralizing antibodies reduced pro-inflammatory gene expression. Our data thus demonstrated for the first time that the absence of functional cystic fibrosis transmembrane conductance regulator (CFTR) at the plasma membrane leads to an intrinsic AP-1, in addition to NF-kappa B, activity and consequently to a pro-inflammatory state sustained through autocrine factors such as IL-1 beta and bFGF. (c) 2007 Elsevier Inc. All rights reserved. [less ▲]