Disease relevance of TNFSF12

• In conclusion, the proinflammatory effects induced by TWEAK on astrocytes in culture recapitulate many characteristics of reactive astrocytes observed in vivo, suggesting that TWEAK could play a significant role in brain inflammation [1].
• These results suggest that TWEAK may be involved in the pathophysiology of periodontal disease [2].
• The role of TWEAK in monocytes in relation to atherogenesis was investigated by analyzing the cellular events induced by TWEAK in a human macrophage-like cell line, THP-1 [3].
• Either TWEAK treatment or Fn14 overexpression in glioma cells resulted in the activation of NFkappaB and subsequently the translocation of NFkappaB from the cytoplasm to the nucleus [4].
• The apoptotic ligands TRAIL, TWEAK, and Fas ligand mediate monocyte death induced by autologous lupus T cells [5].

Psychiatry related information on TNFSF12

• DATA SOURCES: We searched MEDLINE from 1966 to July 1997 for alcoholism or alcohol-drinking and for CAGE, AUDIT, BMAST, TWEAK, T-ACE, MAST, SMAST, or SAAST; Citations Indexes for newer screening questionnaires and those without acronyms; and MEDLINE from 1996 to July 1997 for alcoholism or alcohol-drinking and screening [6].
• The TWEAK and Alcohol Use Disorders Identification Test (AUDIT) questionnaires had high AUROCs (0.87-0.93) for past-year alcohol abuse or dependence in black or white women, but had sensitivities less than 80% at traditional cut points [6].
• TWEAK is an acronym for Tolerance (T1 number of drinks to feel high; T2, number of drinks one can hold), Worry about drinking, Eye-opener (morning drinking), Amnesia (blackouts), and Cut down on drinking (K/C) [7].
• Assessing alcohol misuse during pregnancy: evaluating psychometric properties of the CAGE, T-ACE and TWEAK in a Brazilian setting [8].
• Measures of provider advice on alcohol consumption, demographic characteristics, caffeine intake, smoking, other drug use, alcohol risk (using the TWEAK scale), and depressive symptoms on the Center for Epidemiological Studies Depression Scale (CES-D) were collected [9].

High impact information on TNFSF12

• Five different assays demonstrate TWEAK-TweakR binding, and the interaction affinity constant (Kd) is within a physiologically relevant range of 2.3 +/- 0.1 nM [10].
• These results revealed a novel pathway of monocyte cytotoxicity against tumor cells that is mediated by TWEAK and potentiated by IFN-gamma [11].
• Although freshly isolated PBMCs expressed no detectable level of TWEAK on their surfaces, a remarkable TWEAK expression was rapidly observed on monocytes upon stimulation with interferon (IFN)-gamma but not with IFN-alpha or lipopolysaccharide [11].
• TWEAK, a new member of the tumor necrosis factor (TNF) family, induces cell death in some tumor cell lines, but its physiological functions are largely unknown [11].
• Involvement of TWEAK in interferon gamma-stimulated monocyte cytotoxicity [11].

Chemical compound and disease context of TNFSF12

• Screening measures included questions about cigarettes; questions from the Alcohol Use Disorders Identification Test about consumption (hazardous drinking); the TWEAK test (problem drinking); a drug abuse screen; the Patient Health Questionnaire (psychiatric conditions); and the PTSD (posttraumatic stress disorder) Checklist [12].

Biological context of TNFSF12

• These results indicate that D10 cells induce macrophage apoptosis through TRAIL- and TWEAK-dependent pathways [13].
• Multiple pathways of TWEAK-induced cell death [14].
• Furthermore, TWEAK induced rapid phosphorylation of IkappaB-alpha in human keratinocytes [15].
• Tumour necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK), a member of the TNF family, is a multi-functional cytokine that regulates cellular proliferation, angiogenesis, inflammation and apoptosis [2].
• We further demonstrated that TWEAK induced the production of matrix metalloproteases in human chondrocytes and potently inhibited chondrogenesis and osteogenesis using in vitro models [16].

Anatomical context of TNFSF12

• Further studies demonstrated that AE7, a cloned Th1 line, and splenic T cells express TWEAK, TRAIL, and Fas ligand, and inhibiting these molecules also inhibited macrophage killing [13].
• In this study, we characterized the TWEAK-induced cell death in several tumor cell lines that exhibited distinct features [14].
• Although a pan-caspase inhibitor, benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone, inhibited the TWEAK-induced cell death in HSC3 cells, it rather sensitized HT-29 cells to TWEAK-induced cell death by necrosis [14].
• During the process of TWEAK-induced necrosis, cathepsin B was released from lysosome to cytosol [14].
• Primary cultured normal human keratinocytes constitutively expressed a TWEAK receptor, fibroblast growth factor-inducible 14 (Fn14), and produced regulated on activation, normal T expressed and secreted (RANTES) upon TWEAK stimulation in a concentration-dependent manner [15].

Associations of TNFSF12 with chemical compounds

• TNF-like weak inducer of apoptosis (TWEAK), a member of the tumor necrosis factor (TNF) family, is a multifunctional cytokine that regulate cellular proliferation, angiogenesis, inflammation, and apoptosis [15].
• CEM cells did not differentially express any one of the TNFalpha-homologous receptors investigated nor TNF-related apoptosis-inducing ligand or TNF-related weakly apoptosis-inducing ligand (TWEAK) in the presence of doxorubicin [17].
• TWEAK alone induced cell death in SW480 cells and induced cell death of HT-29 cells after addition of IFN-gamma, actinomycin D or cycloheximide [18].
• Three new tests, the Alcohol Use Disorders Identification Test, the Adolescent Drinking Index, and the TWEAK also are promising [19].
• We have analyzed the expression of Fn14 and its ligand TWEAK in carotid atherosclerotic plaques and its potential modulation by atorvastatin in vivo [20].

Physical interactions of TNFSF12

• Finally, cells isolated from WSL-1/TRAMP knockout mice are shown to retain their ability to interact with TWEAK [21].
• TWEAK acts via binding to a recently identified TNF receptor superfamily member named fibroblast growth factor-inducible 14 (Fn14) [22].
• We show dose-dependent TWEAK binding to CD163 and blockade by an anti-CD163 Ab [23].

Regulatory relationships of TNFSF12

• The TWEAK-induced RANTES production was abrogated by anti-Fn14 antibody, and synergistically augmented by simultaneous stimulation with transforming growth factor-beta [15].
• On the other hand, the TWEAK-induced VCAM-1 expression was inhibited by TGF-beta1 [2].
• The ICAM-1 expression induced by TWEAK was augmented by TGF-beta1 [2].
• TWEAK-induced activation of MMP-9 was mediated by activation of NF-kappaB [3].
• These results suggest that TWEAK is involved in atherosclerosis by inducing pro-inflammatory cytokines and extracellular matrix degrading enzymes, which reduce plaque stability [3].

Other interactions of TNFSF12

• TWEAK (Apo-3 ligand) is a recently identified member of the TNF family that is produced mainly by leukocytes that can infiltrate the inflamed brain and thus influence astrocyte behavior [1].
• Induction of RANTES by TWEAK/Fn14 interaction in human keratinocytes [15].
• Moreover, in combination with IL-1beta or TGF-beta1, TWEAK may be related to the exacerbation of periodontal disease to induce proinflammatory cytokines and adherent molecules by HGF [2].
• These results suggest that WSL-1/TRAMP is not the major receptor for TWEAK[21]
• We demonstrate that TWEAK is a potent inducer of endothelial cell survival and cooperates with basic fibroblast growth factor to induce the proliferation and migration of human endothelial cells and morphogenesis of capillary lumens [24].

Analytical, diagnostic and therapeutic context of TNFSF12

• Reverse transcription-polymerase chain reaction (RT-PCR) analysis and immunohistochemistry revealed that TWEAK and the TWEAK receptor, fibroblast growth factor-inducible 14 (Fn14), mRNA and protein were expressed in periodontally diseased tissues [2].
• In this study, we report that the serum TWEAK level was dramatically elevated during mouse collagen-induced arthritis (CIA) and blocking TWEAK by a neutralizing mAb significantly reduced the clinical severity of CIA [16].
• Soluble TWEAK was detected in culture medium of these cell lines by ELISA and conditioned medium from SW480 cells incubated with anti-TWEAK antibody significantly inhibited endothelial cell tube formation in Matrigels [18].
• All four human colonic adenocarcinoma cell lines constitutively expressed TWEAK mRNA, protein and membrane-bound TWEAK antigen, as detected by RT-PCR, Western blotting and flow cytometry [18].
• In this report, using RACE, RT-PCR, cDNA library screening and an RNase protection assay, we characterize a hybrid transcript between TWEAK and APRIL mRNAs [25].

References