IL-6 in inflammation, immunity, and disease Tanaka, Toshio; Narazaki, Masashi; Kishimoto, Tadamitsu
Cold Spring Harbor perspectives in biology,
10/2014, Volume:
6, Issue:
10
Journal Article
Peer reviewed
Open access
Interleukin 6 (IL-6), promptly and transiently produced in response to infections and tissue injuries, contributes to host defense through the stimulation of acute phase responses, hematopoiesis, and ...immune reactions. Although its expression is strictly controlled by transcriptional and posttranscriptional mechanisms, dysregulated continual synthesis of IL-6 plays a pathological effect on chronic inflammation and autoimmunity. For this reason, tocilizumab, a humanized anti-IL-6 receptor antibody was developed. Various clinical trials have since shown the exceptional efficacy of tocilizumab, which resulted in its approval for the treatment of rheumatoid arthritis and juvenile idiopathic arthritis. Moreover, tocilizumab is expected to be effective for other intractable immune-mediated diseases. In this context, the mechanism for the continual synthesis of IL-6 needs to be elucidated to facilitate the development of more specific therapeutic approaches and analysis of the pathogenesis of specific diseases.
Interleukin-6 (IL-6) is a prototypical cytokine featuring functional pleiotropy
and redundancy. Under situations of stress, such as infection or tissue injury,
IL-6 is rapidly synthesized and plays a ...major role in host defense. However,
uncontrolled excessive or persistent production of IL-6 has a pathological
effect in various diseases. Thus, IL-6 blockade was expected to become a novel
therapeutic strategy for IL-6–mediated inflammatory diseases, and the
first-in-class IL-6 inhibitor tocilizumab, which blocks IL-6 activity by
inhibiting IL-6 binding to its receptor, was developed. Clinical trials of
tocilizumab have verified its efficacy and tolerable safety profile in several
diseases, and it has been approved for the treatment of patients with rheumatoid
arthritis, Castleman's disease, systemic and polyarticular juvenile idiopathic
arthritis, and giant cell arteritis. Off-label use and clinical trials strongly
indicate that tocilizumab will be applicable for a wide variety of acute and
chronic inflammatory diseases.
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Although VEGF-B was discovered as a VEGF-A homolog a long time ago, the angiogenic effect of VEGF-B remains poorly understood with limited and diverse findings from different groups. Notwithstanding, ...drugs that inhibit VEGF-B together with other VEGF family members are being used to treat patients with various neovascular diseases. It is therefore critical to have a better understanding of the angiogenic effect of VEGF-B and the underlying mechanisms. Using comprehensive in vitro and in vivo methods and models, we reveal here for the first time an unexpected and surprising function of VEGF-B as an endogenous inhibitor of angiogenesis by inhibiting the FGF2/FGFR1 pathway when the latter is abundantly expressed. Mechanistically, we unveil that VEGF-B binds to FGFR1, induces FGFR1/VEGFR1 complex formation, and suppresses FGF2-induced Erk activation, and inhibits FGF2-driven angiogenesis and tumor growth. Our work uncovers a previously unrecognized novel function of VEGF-B in tethering the FGF2/FGFR1 pathway. Given the anti-angiogenic nature of VEGF-B under conditions of high FGF2/FGFR1 levels, caution is warranted when modulating VEGF-B activity to treat neovascular diseases.
Persistent and excess IL-6 production often contributes to a variety of immune diseases. IL-6-targeting therapy was first approved for Castleman disease, then rheumatoid arthritis, and now it is ...broadly used. Furthermore, it has been approved not only for chronic and acute inflammatory diseases but also for autoantibody-induced diseases such as neuromyelitis optica spectrum disorder and interstitial lung disease due to systemic sclerosis.
This review summarizes laboratory changes after IL-6 inhibition and molecular changes in the immune cell. A wide range of diseases is discussed, from those for which the efficacy of IL-6-targeting therapy is approved worldwide to those for which only a small number of clinical cases have been reported. It summarizes the characteristics of the diseases for which IL-6-targeting therapy is expected to be effective.
Clinical evidence has demonstrated that IL-6-targeting therapy is relatively safe; however, it is necessary to be cognizant of early detection of infectious disease, as inhibition of IL-6 masks inflammation. Although many of the cases for which IL-6-targeting therapy was effective or partially effective still require validation through clinical trials, the therapy is suggested as a candidate treatment option for various refractory immune diseases.
The signalling pathway that comprises JAK kinases and STAT proteins (for signal transducer and activator of transcription) is important for relaying signals from various cytokines outside the cell to ...the inside. The feedback mechanism responsible for switching off the cytokine signal has not been elucidated. We now report the cloning and characterization of an inhibitor of STAT activation which we name SSI-1 (for STAT-induced STAT inhibitor-1). We found that SSI-1 messenger RNA was induced by the cytokines interleukins 4 and 6 (IL-4, IL-6), leukaemia-inhibitory factor (LIF), and granulocyte colony-stimulating factor (G-CSF). Stimulation by IL-6 or LIF of murine myeloid leukaemia cells (M1 cells) induced SSI-1 mRNA expression which was blocked by transfection of a dominant-negative mutant of Stat3, indicating that the SSI-1 gene is a target of Stat3 (refs 4, 5, 6, 7). Forced overexpression of SSI-1 complementary DNA interfered with IL-6- and LIF-mediated apoptosis and macrophage differentiation of M1 cells, as well as IL-6 induced tyrosine-phosphorylation of a receptor glycoprotein component, gp130, and of Stat3. When SSI-1 is overexpressed in COS7 cells, it can associate with the kinases Jak2 and Tyk2. These findings indicate that SSI-1 is responsible for negative-feedback regulation of the JAK-STAT pathway induced by cytokine stimulation.
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Abstract
Systemic sclerosis (SSc) presents stiffness of extremities due to sclerosis of the tissue especially at fingers, hands, and forearms. Here we report the case of a patient with diffuse ...cutaneous SSc who was administered anti-interleukin-6 receptor antibody tocilizumab (TCZ). Skin condition of SSc is evaluated by pinching the skin according to the Rodnan skin score, but sometimes tissue atrophy results in overestimation of the condition. To understand how the extremities softened after initiation of TCZ, we observed mobility of extremities. Range of motion (ROM) of joints was measured every four months after initiation of TCZ. The patient presented not only reduction of Rodnan score but also amelioration of mobility of extremities. The Rodnan skin score reduced from 35 to 7 within sixteen months, and ROM of most joints except ankle was expanded.
Growth, differentiation, and programmed cell death (apoptosis) are mainly controlled by cytokines. The Janus kinase--signal transducers and activators of transcription (JAK-STAT) signal pathway is an ...important component of cytokine signaling. We have previously shown that STAT3 induces a molecule designated as SSI-1, which inhibits STAT3 functions. To clarify the physiological roles of SSI-1 in vivo, we generated, here, mice lacking SSI-1. These SSI-1-/- mice displayed growth retardation and died within 3 weeks after birth. Lymphocytes in the thymus and spleen of the SSI-1-/- mice exhibited accelerated apoptosis with aging, and their number was 20-25% of that in SSI-1+/+ mice at 10 days of age. However, the differentiation of lymphocytes lacking SSI-1 appeared to be normal. Among various pro- and anti-apoptotic molecules examined, an up-regulation of Bax was found in lymphocytes of the spleen and thymus of SSI-1-/- mice. These findings suggest that SSI-1 prevents apoptosis by inhibiting the expression of Bax.
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Interleukin-6 (IL-6), produced by a variety of cells, is a typical cytokine featuring redundancy and pleiotropic activity. IL-6 is promptly and transiently synthesized in response to infections or ...injuries, and participates in host defense by inducing immune responses, hematopoiesis, and acute-phase reactions. However, since its abnormal persistent production of mostly unknown etiology plays an important pathological role in the development of various immune-mediated diseases, a humanized anti-IL-6 receptor monoclonal antibody, tocilizumab, was developed and is now used as an innovative biologic for rheumatoid arthritis in more than 90 countries. Several factors strongly suggest that a IL-6 blockade strategy may have a broad application for the treatment of various immune-mediated diseases. These factors include favorable results of pilot or case studies with off-label use of tocilizumab, pathological analyses of the contribution of IL-6 to the development of immune-mediated diseases, and the potential capability of tocilizumab to both repair an imbalance of effector T cell subsets and to suppress pathologic autoantibody production. However, clinical trials to evaluate the efficacy and safety of tocilizumab for these diseases are essential. Furthermore, clarification of the cell source of IL-6 production and of the mechanisms through which dysregulated continuous IL-6 synthesis is induced constitutes an important issue for future studies into the pathogenesis of diseases.
Signal transducers and activators of transcription (STAT)-induced STAT inhibitor-1 SSI-1; also known as suppressor of cytokine signaling-1 (SOCS-1) was identified as a negative feedback regulator of ...Janus kinase-STAT signaling. We previously generated mice lacking the SSI-1 gene (SSI-1 -/-) and showed that thymocytes and splenocytes in SSI-1 -/- mice underwent accelerated apoptosis. In this paper, we show that murine embryonic fibroblasts lacking the SSI-1 gene are more sensitive than their littermate controls to tumor necrosis factor-α (TNF-α )-induced cell death. In addition, L929 cells forced to express SSI-1 (L929/SSI-1), but not SSI-3 or SOCS-5, are resistant to TNF-α -induced cell death. Furthermore L929/SSI-1 cells treated with TNF-α sustain the activation of p38 mitogen-activated protein (MAP) kinase. In contrast, SSI-1 -/- murine embryonic fibroblasts treated with TNF-α show hardly any activation of p38 MAP kinase. These findings suggest that SSI-1 suppresses TNF-α -induced cell death, which is mediated by p38 MAP kinase signaling.
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