Tartaglia LA, Weber RF, Figari IS, Reynolds C, Palladino Jr MA, Goeddel DVThe two different receptors for tumor necrosis factor mediate distinct cellular responses. Proc Natl Acad Sci USA 88:9292-9296

Department of Molecular Biology, Genentech, Inc., South San Francisco, CA 94080.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 11/1991; 88(20):9292-6. DOI: 10.1073/pnas.88.20.9292
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The individual roles of the murine type 1 and type 2 tumor necrosis factor (TNF) receptors (TNF-R1 and TNF-R2) were investigated utilizing (i) the strong species specificity of TNF-R2 for murine TNF compared to human TNF and (ii) agonistic rabbit polyclonal antibodies directed against the individual TNF receptors. Proliferation of mouse thymocytes and the murine cytotoxic T-cell line CT-6 is stimulated by murine TNF but not by human TNF. Consistent with this observation, polyclonal antibodies directed against TNF-R2 induced proliferation in both of these cell types, whereas polyclonal antibodies directed against TNF-R1 had no effect. In contrast, cytotoxicity in murine LM cells (which are sensitive to murine and human TNF) was induced by antibodies against TNF-R1 but not by antibodies against TNF-R2. Also, the steady-state level of manganous superoxide dismutase mRNA in the murine NIH 3T3 cell line was induced by murine TNF, human TNF, and anti-TNF-R1 but not by anti-TNF-R2. These results suggest that TNF-R2 initiates signals for the proliferation of thymocytes and cytotoxic T cells, whereas TNF-R1 initiates signals for cytotoxicity and the induction of the protective activity, manganous superoxide dismutase. The nonredundant signaling observed for the two TNF receptors cannot be explained simply by the differential expression of the two TNF receptors in the various cell types, because LM cells express on their surface higher levels of TNF-R2 than TNF-R1, and LM cells, NIH 3T3 cells, and thymus cells all express mRNA corresponding to both receptor types. It is therefore likely that the two receptors initiate distinct signaling pathways that result in the induction of different cellular responses.

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Available from: Dave Goeddel, Sep 29, 2015
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    • "It has been shown that each receptor has a different signal transduction pathway thus; it has unique downstream intracellular processes (Vilcek and Lee, 1991). Tartaglia et al. (1991), Rothe et al. (1994) and Hsu et al. (1996) observed that the cell responding to TNF is completely dependent on the type of TNF receptor which is predominant on the cell surface. Hohmann et al. (1989) and Ware et al. (1991) stated that most of the cells express both TNFR1 and 2 on their surface, however; in general, one of these two receptors is predominantly expressed. "
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    ABSTRACT: In this study, a complete molecular characterization of tumor necrosis factor receptor 1 (TNFR1) which was identified from the constructed cDNA library of striped murrel Channa striatus (Cs) is reported. The CsTNFR1 encoded a type I membrane receptor protein that contains 399 amino acids including three cysteine-rich domains (CRDs) at CRD1(41-46), CRD2(79-118) and CRD3(120-159) in the extracellular region and a putative TNF receptor-associated factor (TRAF) site at 245-253 and a death domain between 297 and 388 in the cytoplasmic region which is essential for induction of apoptosis. The predicted molecular mass of CsTNFR1 is 45kDa and its corresponding theoretical isoelectric point (pI) is 6.3. CsTNFR1 shared maximum identity with TNFR1 from olive flounder Paralichthys olivaceus (82%). Real-time PCR showed that CsTNFR1 gene was expressed most abundantly (P<0.05) in the head kidney. Further, CsTNFR1 mRNA transcription was studied after challenge with fungus Apanomyces invadans and bacteria Aeromonas hydrophila. The fungus injected murrels showed a highest expression at 48h, whereas bacteria injected murrels showed at 24h. The gene expression studies revealed that CsTNFR1 may be involved in innate immune process of murrels against pathogenic infections. The over-expressed and purified recombinant CsTNFR1 protein (rCsTNFR1) was subjected to TNF-α inhibition assay to confirm their specificity and activity against TNF-α which confirmed that the rCsTNFR1 inhibits the activity of TNF-α in a dose dependent manner where maximum inhibition (97%) was observed at 10,000 fold concentration of rCsTNFR1. In addition, the direct cytotoxic effect of rCsTNFR1 was analyzed against head kidney phagocyte. The results showed that the recombinant CsTNFR1 protein does not exhibit any significant cytotoxicity against head kidney phagocyte cells even at higher concentration (8μg/ml). Moreover, the recombinant protein was analyzed for respiratory burst activity in the presence of two different ROS inducers, opsonized zymosan (fungal cell wall component) and phorbol 12-myristate 13-acetate (PMA). The findings showed that the C. striatus head kidney phagocyte exposed to purified recombinant CsTNFR1 protein alone do not produced any ROS. However, opsonized zymosan induced recombinant CsTNFR1 protein significantly (P<0.05) enhanced the ROS production on concentration basis which is revealed that the ROS production depends on the concentration of the recombinant CsTNFR1 protein. Overall, the study showed that the CsTNFR1 plays an important role in the pathogen-induced inflammatory process of striped murrel. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Molecular Immunology 04/2015; 66(2):240-252. DOI:10.1016/j.molimm.2015.03.015 · 2.97 Impact Factor
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    • "In particular, it is interesting to note that the same compounds are able to elicit opposite effects, either neuroprotective or neurotoxic/apoptotic, usually through the interaction with distinct receptors, and the consequent activation of different molecular cascades(Kinouchi et al., 1991; Tartaglia et al., 1991) (Petitto et al., 1997). Some of the most interesting aspects of IL-1, IL-2, IL-6, IL-8, TNFα and INFs are reported in the table below. "
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    ABSTRACT: The pathophysiology of Bipolar Disorder (BD) is yet to be fully characterized. In the last years attention was focused on neurodevelopment or neurodegenerative events. In this context, hyper- and hypo- activation of inflammatory cascades may play a role in modulating the architecture and function of neuronal tissues. In the present paper we tested the enrichment of molecular pathways related to inflammatory cascades (IL-1, IL-2, IL-6, IL-8, TNF and INF) testing whether genes related to these systems hold more variations associated with the risk for BD than expected. ~7000 bipolar patients and controls with genome-wide data available from NIMH dataset were analyzed. SNPs were imputed, checked for quality control, pruned and tested for association (0.01<p). Fisher test was conducted to test the enrichment within the pathways and the association was permutated (10(5) times) to limit false positive findings. As a result, IL-6, IL-8 and IFN related pathways held twice to thrice the number of expected variants associated with BD. These tests resisted the permutation analysis. The restricted number of inflammatory components included in the analysis and the lack of functional consequences for some of the SNPs analyzed may be biased; however, these choices helped the authors to lighten the statistical computational load for the analyses and at the same time included possibly hidden SNPs in linkage disequilibrium with the analyzed variations. We bring evidence that the inflammatory cascades may be genetically varied in Bipolar patients. This genetic background may explain part of the pathophysiology of the disorder. Copyright © 2015 Elsevier B.V. All rights reserved.
    Journal of Affective Disorders 03/2015; 179:88-94. DOI:10.1016/j.jad.2015.03.032 · 3.38 Impact Factor
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    • "TNFR1 is ubiquitously expressed on the lymphoid system and nearly all cells of the body, which likely accounts for TNF’s wide-ranging functions. TNFR2 is expressed in a more limited manner on certain populations of lymphocytes, including T-regulatory cells (Tregs) (2, 3), endothelial cells, microglia, neuron subtypes (4, 5), oligodendrocytes (6, 7), cardiac myocytes (8), thymocytes (9, 10), islets of Langerhans (personal communication, Faustman Lab), and human mesenchymal stem cells (11). Its more restricted cellular expression makes TNFR2 more attractive than TNFR1 as a molecular target for drug development. "
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    ABSTRACT: THE REGULATORY CYTOKINE TUMOR NECROSIS FACTOR (TNF) EXERTS ITS EFFECTS THROUGH TWO RECEPTORS: TNFR1 and TNFR2. Defects in TNFR2 signaling are evident in a variety of autoimmune diseases. One new treatment strategy for autoimmune disease is selective destruction of autoreactive T cells by administration of TNF, TNF inducers, or TNFR2 agonism. A related strategy is to rely on TNFR2 agonism to induce T-regulatory cells (Tregs) that suppress cytotoxic T cells. Targeting TNFR2 as a treatment strategy is likely superior to TNFR1 because of its more limited cellular distribution on T cells, subsets of neurons, and a few other cell types, whereas TNFR1 is expressed throughout the body. This review focuses on TNFR2 expression, structure, and signaling; TNFR2 signaling in autoimmune disease; treatment strategies targeting TNFR2 in autoimmunity; and the potential for TNFR2 to facilitate end organ regeneration.
    Frontiers in Immunology 12/2013; 4:478. DOI:10.3389/fimmu.2013.00478
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