First described as a weak apoptosis inducer, the TNF superfamily ligand TWEAK has since emerged as a cytokine that regulates multiple cellular responses, including proinflammatory activity, angiogenesis and cell proliferation, suggesting roles in inflammation and cancer. More recently TWEAK's ability to regulate progenitor cell fate was elucidated. Experiments using genetic overexpression and pathway inhibition or deficiency in mice indicate that TWEAK coordinates inflammatory and progenitor cell responses in settings of acute injury through its highly inducible receptor, FGF-inducible molecule 14 (Fn14), establishing the pathway's physiological role in facilitating acute tissue repair. In contrast, in chronic inflammatory disease models characterized by persistent TWEAK/Fn14 activation, TWEAK functions as a novel pathogenic mediator by amplifying inflammation, promoting tissue damage and potentially impeding endogenous repair mechanisms. Herein we aim not only to review the multifaceted functions of this emerging pathway, but also propose a conceptual framework for TWEAK/Fn14 pathway function in health and disease, supported by studies employing TWEAK and Fn14 deficient mice and anti-TWEAK blocking mAbs in acute injury and inflammatory disease settings. In addition to a perspective of the biology, we discuss potential therapeutic strategies targeting this pathway for the treatment of tissue injury, chronic inflammatory diseases and cancer.
"However, ligands of the TNF family control the immune and inflammatory responses at several levels, and other molecules can influence TNF-alpha synthesis and release, such as the two new TNF superfamily ligands: TNF-related weak inducer of apoptosis (TWEAK) and TNF-related apoptosis-inducing Ligand (TRAIL) (Tansey and Szymkowski, 2009). TWEAK, also known as Apo3L or TNFSF12, mediates different immune responses and one of its functions is to attenuate the transition from innate to adaptive immunity (Burkly et al., 2007), balancing TNF activity by repressing the production of pro-inflammatory cytokines such as IFN-g and IL-12 (Maecker et al., 2005). TRAIL (Apo2L or TNFSF10), acts by triggering the extrinsic apoptotic pathway by interacting with death receptors DR4 (TRAILR1) and DR5 (TRAILR2) and is also capable of inducing apoptosis in cancer cells and seems to be involved in tumor suppression and immune cell homeostasis (Falschlehner et al., 2009; Wajant, 2004; Wang and El-Deiry, 2003). "
[Show abstract][Hide abstract] ABSTRACT: Background
Both early life stress (ELS) and substance abuse, especially cocaine, have robust effects on the inflammatory system. Considering the role of the tumor necrosis factor system in inflammatory signaling and its association with ELS, the aim of the study was to compare plasma levels of TNF-alpha, its soluble receptors and ligands during early abstinence of crack cocaine.
This study included 24 crack cocaine-dependent women with (CRACK-ELS) and 20 without (CRACK) a history of ELS. A healthy control group (HC), containing 25 participants, was included to provide reference values. The Childhood Trauma Questionnaire (CTQ) retrospectively assessed childhood maltreatment history of patients. Plasma levels of TNF-alpha, TNF-related weak inducer of apoptosis (TWEAK), TNF-related apoptosis-inducing ligand (TRAIL), soluble receptors TNFRI (sTNFRI) and TNFRII (sTNFRII) were assessed on the 18th day of treatment.
The CRACK-ELS group had higher TNF-alpha and lower TWEAK levels compared to the CRACK and HC groups. sTNFRII was increased, but only in comparison with the crack cocaine group and the controls. TRAIL levels were slightly higher in the CRACK-ELS group, while no differences were found for sTNFRI levels. Also, TNF-alpha plasma level was positively predicted by abstinence severity and childhood maltreatment severity, and TWEAK was negatively predicted by childhood maltreatment severity.
This is the first study to evaluate the newly secreted tumor necrosis factor superfamily ligands, TWEAK and TRAIL, during crack cocaine abstinence, supporting the association between early life stress and peripheral pro-inflammatory levels.
Journal of Psychiatric Research 06/2014; DOI:10.1016/j.jpsychires.2014.02.017 · 3.96 Impact Factor
"However, the activities of these proinflammatory cytokines depend on the involved cell types and its microenvironment. For example, after an “acute” injury, tumor necrosis factor-like weak inducer of apoptosis (TWEAK) promotes tissue regeneration by stimulating progenitor cells but in “chronic” diseases where TWEAK is persistently activated it alters tissue repair by inhibiting differentiation of the same progenitor cells [22, 23]. The inflammatory pathways are clearly complex and dependent on many conditions (e.g., acute versus chronic, microenvironment) and therefore are often difficult to clearly characterise. "
[Show abstract][Hide abstract] ABSTRACT: Inflammation at both systemic and local intraperitoneal levels commonly affects peritoneal dialysis (PD) patients. Interest in inflammatory markers as targets of therapeutic intervention has been considerable as they are recognised as predictors of poor clinical outcomes. However, prior to embarking on strategies to reduce inflammatory burden, it is of paramount importance to define the underlying processes that drive the chronic active inflammatory status. The present review aims to comprehensively describe clinical causes of inflammation in PD patients to which potential future strategies may be targeted.
International Journal of Nephrology 05/2014; 2014:909373. DOI:10.1155/2014/909373
"TWEAK interacts with target cells via its receptor, fibroblast growth factor-inducible 14 (Fn14) (29), which is highly homologous in mouse and human tissues, and is upregulated in HCC lines and tissues (30). Biologically, TWEAK has been shown to regulate numerous cellular processes including proliferation, differentiation, migration, and cell survival and has also been described as a pro-angiogenic and pro-inflammatory factor (31). In chronic liver injury and repair, the principal function of TWEAK appears to initiate ductal proliferation and LPC expansion via activation of NFκB signaling. "
[Show abstract][Hide abstract] ABSTRACT: Chronic liver diseases (CLD) such as hepatitis B and C virus infection, alcoholic liver disease, and non-alcoholic steatohepatitis are associated with hepatocellular necrosis, continual inflammation, and hepatic fibrosis. The induced microenvironment triggers the activation of liver-resident progenitor cells (LPCs) while hepatocyte replication is inhibited. In the early injury stages, LPCs regenerate the liver by proliferation, migration to sites of injury, and differentiation into functional biliary epithelial cells or hepatocytes. However, when this process becomes dysregulated, wound healing can progress to pathological fibrosis, cirrhosis, and eventually hepatocellular carcinoma. The other key mediators in the pathogenesis of progressive CLD are fibrosis-driving, activated hepatic stellate cells (HSCs) that usually proliferate in very close spatial association with LPCs. Recent studies from our group and others have suggested the potential for cytokine and chemokine cross-talk between LPCs and HSCs, which is mainly driven by the tumor necrosis factor (TNF) family members, TNF-like weak inducer of apoptosis (TWEAK) and lymphotoxin-β, potentially dictating the pathological outcomes of chronic liver injury.
Frontiers in Immunology 02/2014; 5:39. DOI:10.3389/fimmu.2014.00039
Jeroen Baardman, Iris Licht, Menno PJ de Winther, Jan Van den Bossche,
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