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      Interferon-γ is a master checkpoint regulator of cytokine-induced differentiation

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          Significance

          The understanding of the molecular mechanisms of activation and checkpoint processes has important therapeutic implications. Here, we show that interferon-γ is a master checkpoint regulator for many cytokines. It operates partially by activating STAT1 signaling. However, most important is the mechanism that allows it to assume master regulator status. To do this, it induces internalization of gp130, a common component of many heterodimeric cytokine receptors. Therefore, this cytokine checkpoint could open a whole new paradigm in cell biology.

          Abstract

          Cytokines are protein mediators that are known to be involved in many biological processes, including cell growth, survival, inflammation, and development. To study their regulation, we generated a library of 209 different cytokines. This was used in a combinatorial format to study the effects of cytokines on each other, with particular reference to the control of differentiation. This study showed that IFN-γ is a master checkpoint regulator for many cytokines. It operates via an autocrine mechanism to elevate STAT1 and induce internalization of gp130, a common component of many heterodimeric cytokine receptors. This targeting of a receptor subunit that is common to all members of an otherwise diverse family solves the problem of how a master regulator can control so many diverse receptors. When one adds an autocrine mechanism, fine control at the level of individual cells is achieved.

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          Most cited references30

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          An overview of the immune system.

          We are continually exposed to organisms that are inhaled, swallowed, or inhabit our skin and mucous membranes. Whether these organisms penetrate and cause disease is a result of both the pathogenicity of the organism (the virulence factors at its disposal) and the integrity of host defence mechanisms. The immune system is an interactive network of lymphoid organs, cells, humoral factors, and cytokines. The essential function of the immune system in host defence is best illustrated when it goes wrong; underactivity resulting in the severe infections and tumours of immunodeficiency, overactivity in allergic and autoimmune disease. In this review we have covered the normal function of the immune system in recognising, repelling, and eradicating pathogens and other foreign molecules.
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            Mesenchymal Stem Cell-Based Tissue Regeneration is Governed by Recipient T Lymphocyte via IFN-γ and TNF-α

            Stem cell-based regenerative medicine is a promising approach for tissue reconstruction. Here, we showed that pro-inflammatory T cells in the recipients inhibited bone marrow mesenchymal stem cell (BMMSC)-mediated bone formation via T helper 1 (Th1) cytokine interferon (IFN)-γ induced down-regulation of runt-related transcription factor 2 (Runx-2) pathway and tumor necrosis factor (TNF)-α-regulated BMMSC apoptosis. TNF-α converted IFN-γ-activated non-apoptotic Fas to a caspase 3/8-associated apoptotic signaling in BMMSCs through inhibition of nuclear factor kappa B (NFκB), resulting in BMMSC apoptosis. Conversely, reduction of IFN-γ and TNF-α levels by systemic infusion of Foxp3+ regulatory T cells (Tregs) markedly improved BMMSC-based bone regeneration and calvarial defect repair in C57BL6 mice. Furthermore, we showed that local administration of aspirin reduced levels of IFN-γ and TNF-α at the implantation site and significantly improved BMMSC-based calvarial defect repair. These data collectively uncover a previously unrecognized role of recipient T cells in BMMSC-based tissue engineering.
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              Novel regulators of bone formation: molecular clones and activities

              Protein extracts derived from bone can initiate the process that begins with cartilage formation and ends in de novo bone formation. The critical components of this extract, termed bone morphogenetic protein (BMP), that direct cartilage and bone formation as well as the constitutive elements supplied by the animal during this process have long remained unclear. Amino acid sequence has been derived from a highly purified preparation of BMP from bovine bone. Now, human complementary DNA clones corresponding to three polypeptides present in this BMP preparation have been isolated, and expression of the recombinant human proteins have been obtained. Each of the three (BMP-1, BMP-2A, and BMP-3) appears to be independently capable of inducing the formation of cartilage in vivo. Two of the encoded proteins (BMP-2A and BMP-3) are new members of the TGF-beta supergene family, while the third, BMP-1, appears to be a novel regulatory molecule.
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                Author and article information

                Journal
                Proc Natl Acad Sci U S A
                Proc. Natl. Acad. Sci. U.S.A
                pnas
                pnas
                PNAS
                Proceedings of the National Academy of Sciences of the United States of America
                National Academy of Sciences
                0027-8424
                1091-6490
                15 August 2017
                31 July 2017
                31 July 2017
                : 114
                : 33
                : E6867-E6874
                Affiliations
                [1] aDepartment of Chemistry, The Scripps Research Institute , La Jolla, CA 92037;
                [2] bDepartment of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, CA 92037
                Author notes
                1To whom correspondence may be addressed. Email: kyungmoo@ 123456scripps.edu or rlerner@ 123456scripps.edu .

                Contributed by Richard A. Lerner, July 11, 2017 (sent for review April 27, 2017; reviewed by Domineco Accili and Douglas A. Melton)

                Author contributions: Z.Z., K.Y., and R.A.L. designed research; Z.Z., F.B., A.N., and T.Z. performed research; Z.Z., H.Z., K.Y., and R.A.L. analyzed data; and Z.Z., K.Y., and R.A.L. wrote the paper.

                Reviewers: D.A., Columbia University; and D.A.M., Harvard University.

                Article
                PMC5565454 PMC5565454 5565454 201706915
                10.1073/pnas.1706915114
                5565454
                28760993
                b1400c30-0bf8-407f-afd8-c9b0d369d4e1

                Freely available online through the PNAS open access option.

                History
                Page count
                Pages: 8
                Categories
                PNAS Plus
                Biological Sciences
                Developmental Biology
                PNAS Plus

                interferon-γ,master regulator,checkpoint,cytokine,differentiation

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