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TNF Superfamily Linking Autoimmune Diseases, TNF Inflammation and Cancer

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TNF Superfamily Linking Autoimmune Diseases, TNF Inflammation and Cancer International Edition www.adipogen.com XPERTS E TNF Superfamily Linking Autoimmune Diseases, TNF Inflammation and Cancer THE Adipogen's Team has 15 years of experience in manufacturing TNF superfamily reagents. This expertise has been acquired by an established long-term collaboration with renowned labs of key players in the field including Professor Jürg Tschopp, who first cloned the TNF superfamily ligands BAFF and APRIL. The tumor necrosis factor (TNF) superfamily (TNFSF) is composed of 19 structurally related proteins (ligands) that bind to one or more molecules from the TNF receptor superfamily (TNFRSF), a family of 30 structurally similar receptors. The TNFSF ligands are either membrane-anchored or soluble trimers that cluster their cognate cell surface receptors to initiate signal transduction. The unique structural features of the TNFSF ligands and receptors link these molecules to cell growth, cell survival or cell death, although some molecules can activate both inflammatory and cell death pathways, dependent on target cell types and other extrinsic stimuli. Many of the TNFRSF molecules are expressed in cells of the immune system, which implies that they may be central to autoimmune and inflammatory diseases as well as cancer. However, their function is not restricted to immune cells, members of these superfamilies have been linked to an array of pathophysiologies, including cancer, neurologic diseases, cardiovascular diseases, pulmonary diseases, autoimmune diseases and metabolic diseases. TNFSF and TNFRSF genes have been found to display polymorphisms that are linked to human diseases, which implies that interventions targeting these molecules may be efficacious in treating several health-related problems. Therefore, it is not surprising that several biologics targeting TNFSF and TNFRSF molecules are in ongoing clinical trials for autoimmune and inflammatory diseases and cancer. Membrane Membrane TNFSF Soluble TNFSF TNFSF TNFRSF TNFRSF TRADD or FADD TRAFs BAX or BID IKKα, IKKβ, IKKγ IKKα, IKKβ, IKKγ NIK Pro-caspase 8 Pro-caspase 10 Mitochondria IKKα IκBα Caspase-8 MAPK AKT Cytochrome c p50 RELA p100 RELB Pro-caspase-9 Caspase-10 Induction of cell cycle proteins, anti-apoptotic proteins, Induction of apoptosis via activation of inflammatory cytokines and chemokines caspase-3, caspase-6 and caspase-7 FIGURE: Pro-inflammatory and death-inducing activity of TNFSF members. Adapted from M. Croft, et al.; Nat. Rev. Drug Disc. 12, 147 (2013) LIGAND: RECEPTOR: CD40L [TNFSF5] CD40 [TNFRSF5] CD40L (CD154) binds to CD40, which is essential in mediating event in Alzheimer disease pathogenesis. CD40 is constitutive- a broad variety of immune and inflammatory responses in- ly expressed by antigen presenting cells, including dendritic cluding T cell-dependent immunoglobulin class switching, cells, B cells and macrophages. Consistent with its widespread memory B cell development and germinal center formation. expression on normal cells, CD40 is also expressed on a wide The interaction of CD40-CD40L is necessary for amyloid--in- range of tumor cells. CD40L levels are increased in serum and duced microglial activation, and thus is thought to be an early in inflamed tissues of patients with autoimmune diseases. MegaLigands MegaLigands are high activity constructs in which two trimeric TNFSF ligands are artificially linked via the oligo- meric collagen domain of ACRP30. MegaCD40L is a potent B cell activator. MegaCD40L very effectively mimics the natural membrane-assisted aggregation of CD40L. It is the most potent alternative to activate CD40 with the advantage that no oligomerization reagent (enhancer) is required. BULK available! MegaCD40L 90 MegaCD40L, Soluble (human) (rec.) cells 80 MegaCD40L (h) AG-40B-0010-C010 10 μg 70 AG-40B-0010-3010 MultiPack 3 x 10 μg CD40L (h) 60 CD40L (h) + enhancer SOURCE: CHO cells. SEQUENCE: Human CD40L (aa 116-261) is 50 fused at the N-terminus to mouse ACRP30headless (aa 18- 40 111) and a FLAG®-tag. SPECIFICITY: Binds to human CD40. BIOLOGICAL ACTIVITY: Induces B cells activation (as demon- 30 20 strated by dose-dependent upregulation of CD86) (ED50: Percentage /Cd19 posive of CD86 4 0 37 12 ng /ml ENDOTOXIN CONTENT: 333 111 <1ng/ml). <0.01EU/μg purified protein 1,37 0,46 0,15 0,05 0,02 1000 (LAL test; Lonza). FIGURE: MegaCD40L, Soluble (human) (rec.) (Prod. No. AG-40B-0010) LITERATURE REFERENCES: does not need an enhancer to induce B cells activation. IgG subclass switch capacity is low in switched and in IgM-only, but high in METHOD: IgD+IgM+, post-germinal center (CD27+) human B cells: C. Werner-Favre, PBL cells were incubated in 96-well plates (2x105 cells/well in et al.; Eur. J. Immunol. 31, 243 (2001) 100μl RPMI supplemented with 10% FCS) for 24 hours at 37°C with the indicated concentration of MegaCD40L, Soluble (human) (rec.) or CD40L Two adjacent trimeric Fas ligands are required for Fas signaling and (human) in the presence and absence of 1μg/ml Enhancer (Prod. No formation of a death-inducing signaling complex: N. Holler, et al.; Mol. AG-35B-0001). Cells were washed with PBS and stained with 2μl each Cell. Biol. 23, 1428 (2003) CD86-PE and CD19-FITC in 50μl FACS buffer (PBS, 5% fetal calf serum, Impaired CD40L signaling is a cause of defective IL-12 and TNF-alpha 0.02% azide) for 20 min. at 4°C in the dark. After two washes in FACS production in Sezary syndrome: circumvention by hexameric soluble buffer, samples were then analyzed by flow cytometry. CD40L: L.E. French, et al.; Blood 105, 219 (2005) Only available from AdipoGen® www.adipogen.com MegaCD40L, Soluble (mouse) (rec.) MegaCD40L, Soluble (rat) (rec.) AG-40B-0020-C010 10 μg AG-40B-0107-C010 10 μg AG-40B-0020-3010 MultiPack 3 x 10 μg AG-40B-0107-3010 MultiPack 3 x 10 μg BULK available for in vivo studies! Bulk available for in vivo studies! APPLICATIONS: FACS: Flow Cytometry; FUNC: Functional Application; ICC: Immunocytochemistry; FORMULATION: PF = Preservative free 2 IHC: Immunohistochemistry IP: Immunoprecipitation; WB: Western blot SPECIES: Hu = Human; Ms = Mouse; Rt = Rat; Rb = Rabbit; Prm = Primate BULK available! THE STANDARD Mouse CD40 Antibody for in vivo studies Activates B and NK cells in vivo and in vitro& PRODUCT NAME PID SIZE ISOTYPE APPLICATION SPECIES CD40 (mouse), mAb (FGK45) AG-20B-0036 100 μg | 500 μg Rt IgG2a FACS, FUNC (Activation) Ms CD40 (mouse), mAb (FGK45) (PF) AG-20B-0036PF 100 μg | 500 μg Rt IgG2a FACS, FUNC (Activation) Ms www.adipogen.com Human CD40/CD40L Proteins & Antibodies PROTEINS PID SIZE SOURCE ENDOTOXIN SPECIES CD40 (human):Fc (human) (rec.) AG-40B-0083 50 μg | 3 x 50 μg HEK 293 cells <0.1EU/μg Hu, Ms ANTIBODIES PID SIZE ISOTYPE APPLICATION SPECIES CD40 (human), mAb (BE-1) ANC-189-020 100 μg Ms IgG1 ELISA, FACS, FUNC, IP Hu CD40L [CD154] (human), mAb (24-31) ANC-353-020 100 μg Ms IgG1 ELISA, FACS, FUNC Hu, Prm (Blocking), IHC, WB LIGANDS: RECEPTORS: LT [TNFSF3] LTR [TNFRSF3] LIGHT [TNFSF14] HVEM [TNFRSF14] DcR3 [TNFRSF6B] LT (LT12) binds to the LTR activating two different NF- noma HT-29. It also binds to decoy receptor 3 (DcR3) and HVEM. B pathways that lead to distinct patterns of gene induction, B and T lymphocyte associated (BTLA; CD272) is an Ig domain including selected chemokines and the cytokine BAFF, which superfamily member. The herpes virus entry mediator (HVEM; is essential for the survival of mature B lymphocytes. LTR CD270) can act as a molecular switch that modulates T cell activates the classical NF-B (relA/p50) pathway, like the type activation by propagating positive signals from the TNF-re- 1 TNF receptor (TNF-R1), that regulates proinflammatory genes. lated ligand LIGHT, or inhibitory signals through the Ig su- However, LTR, unlike TNF-R1, also activates the processing perfamily member BTLA. The binding site on HVEM for BTLA of p100 to form RelB/p52 complexes, which activate genes is conserved in the orphan TNF receptor UL144, present in involved in lymphoid organ formation and lymphocyte survival. human cytomegalovirus (CMV). UL144 binds BTLA, but not LIGHT (CD258) binds to LTR. It activates NF-B, stimulates the LIGHT, and inhibits T cell proliferation, selectively mimicking proliferation of T cells and inhibits growth of the adenocarci- the inhibitory cosignaling function of HVEM. PROTEINS PID SIZE SOURCE ENDOTOXIN SPECIES BTLA (human)-muIg Fusion Protein ANC-542-020 25 μg CHO cells N/A Hu HVEM (human)-muIg Fusion Protein ANC-531-020 25 μg CHO cells N/A Hu LIGHT, Soluble (human) (rec.) AG-40B-0009 10 μg | 3 x 10 μg CHO cells <0.01EU/μg Hu, Ms LTR (human):Fc (human) (rec.) (non-lytic) CHI-HF-220LTBR 100 μg CHO cells <0.06EU/μg Hu ANTIBODIES PID SIZE ISOTYPE APPLICATION SPECIES BTLA (human), mAb (6F4) AG-20B-0049 100 μg Rt IgG1 ELISA, FACS, Hu FUNC (Inhibition) HVEM (human), mAb (ANC3B7) ANC-270-020 100 μg Ms IgG2a ELISA, FACS Hu LTR (mouse), mAb (3C8) AG-20B-0041 100 μg Rt IgG1 FUNC (Activation) Ms LTR (mouse), mAb (3C8) (PF) AG-20B-0041PF 100 μg Rt IgG1 FUNC (Activation) Ms LTR (mouse), mAb (4H8 WH2) AG-20B-0008 100 μg Rt IgG2a FACS, Ms FUNC (Activation) LTR (human), mAb (ANCLTR2/9E2) ANC-267-020 100 μg Ms IgG1 ELISA, FACS Hu Visit www.adipogen.com for additional preservative free and labeled antibodies! For updated prices and additional information visit www.adipogen.com or contact your local distributor. 3 LIGAND: RECEPTORS: FasL [TNFSF6] Fas [TNFRSF6] DcR3 [TNFRSF6B] FasL (CD95L; CD178) binds to Fas (CD95), a receptor that trans- mediated apoptosis. Stimulation of Fas has also been reported duces the apoptotic signal into cells. It is involved in cytotoxic to trigger non-apoptotic pathways. It has been shown that T cell-mediated apoptosis and in T cell development. The membrane-bound FasL is essential for the cytotoxic activity, formation of the Fas death-inducing signaling complex (DISC) whereas soluble FasL appears to promote autoimmunity and is the initial step of Fas signaling.
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