IL-6 in inflammation, autoimmunity and cancer.

IL-6 is involved both in immune responses and in inflammation, hematopoiesis, bone metabolism and embryonic development. IL-6 plays roles in chronic inflammation (closely related to chronic inflammatory diseases, autoimmune diseases and cancer) and even in the cytokine storm of corona virus disease 2019 (COVID-19). Acute inflammation during the immune response and wound healing is a well-controlled response, whereas chronic inflammation and the cytokine storm are uncontrolled inflammatory responses.

How COVID-19 induces cytokine storm with high mortality.

The newly emerging coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first reported in Wuhan, China, but has rapidly spread all over the world. Some COVID-19 patients encounter a severe symptom of acute respiratory distress syndrome (ARDS) with high mortality. This high severity is dependent on a cytokine storm, most likely induced by the interleukin-6 (IL-6) amplifier, which is hyper-activation machinery that regulates the nuclear factor kappa B (NF-κB) pathway and stimulated by the simultaneous activation of IL-6-signal transducer and activator of transcription 3 (STAT3) and NF-κB signaling in non-immune cells including alveolar epithelial cells and endothelial cells.

Renin-angiotensin system inhibitors and the severity of coronavirus disease 2019 in Kanagawa, Japan: a retrospective cohort study.

Since the beginning of the coronavirus disease 2019 (COVID-19) outbreak initiated on the Diamond Princess Cruise Ship at Yokohama harbor in February 2020, we have been doing our best to treat COVID-19 patients. In animal experiments, angiotensin converting enzyme inhibitors (ACEIs) and angiotensin II type-1 receptor blockers (ARBs) are reported to suppress the downregulation of angiotensin converting enzyme 2 (ACE2), and they may inhibit the worsening of pathological conditions. We aimed to examine whether preceding use of ACEIs and ARBs affected the clinical manifestations and prognosis of COVID-19 patients.

COVID-19: A New Virus, but a Familiar Receptor and Cytokine Release Syndrome.

Zhou et al. (Nature) and Hoffmann et al. (Cell) identify ACE2 as a SARS-CoV-2 receptor, and the latter show its entry mechanism depends on cellular serine protease TMPRSS2.

Mast cells play role in wound healing through the ZnT2/GPR39/IL-6 axis.

Zinc (Zn) is an essential nutrient and its deficiency causes immunodeficiency and skin disorders. Various cells including mast cells release Zn-containing granules when activated; however, the biological role of the released Zn is currently unclear. Here we report our findings that Zn transporter ZnT2 is required for the release of Zn from mast cells.

Pleiotropy and Specificity: Insights from the Interleukin 6 Family of Cytokines.

Since the molecular cloning of interleukin-6 (IL-6) in 1986, many other cytokines have been found to share the same signal transducer, gp130, in their receptor complexes. Thus, the IL-6 family of cytokines now consists of ten members. Although some of the family members' functions are redundant as a result of the expression of gp130, there are also functional distinctions between members.

Naïve T Cell Homeostasis Regulated by Stress Responses and TCR Signaling.

The survival of naïve T cells is believed to require signals from TCR-pMHC interactions and cytokines such as IL-7. In contrast, signals that negatively impact naïve T cell survival are less understood. We conducted a forward genetic screening of mice and found a mutant mouse line with reduced number of naïve T cells (T-Red mice).

A pain-mediated neural signal induces relapse in murine autoimmune encephalomyelitis, a multiple sclerosis model.

Although pain is a common symptom of various diseases and disorders, its contribution to disease pathogenesis is not well understood. Here we show using murine experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis (MS), that pain induces EAE relapse. Mechanistic analysis showed that pain induction activates a sensory-sympathetic signal followed by a chemokine-mediated accumulation of MHC class II+CD11b+ cells that showed antigen-presentation activity at specific ventral vessels in the fifth lumbar cord of EAE-recovered mice.

KDEL receptor 1 regulates T-cell homeostasis via PP1 that is a key phosphatase for ISR.

KDEL receptors are responsible for retrotransporting endoplasmic reticulum (ER) chaperones from the Golgi complex to the ER. Here we describe a role for KDEL receptor 1 (KDELR1) that involves the regulation of integrated stress responses (ISR) in T cells. Designing and using an N-ethyl-N-nitrosourea (ENU)-mutant mouse line, T-Red (naïve T-cell reduced), we show that a point mutation in KDELR1 is responsible for the reduction in the number of naïve T cells in this model owing to an increase in ISR.

Zinc-binding metallothioneins are key modulators of IL-4 production by basophils.

Zinc (Zn) is an essential nutrient, and Zn deficiency causes immunodeficiency and skin disorders. Basophils express FcɛRI on their surface and release multiple mediators after receptor cross-linking, including large amounts of IL-4. However, the mechanisms involved in the FcɛRI-mediated regulation of basophil IL-4 production are currently unclear.

Temporal expression of growth factors triggered by epiregulin regulates inflammation development.

In this study, we investigated the relationship between several growth factors and inflammation development. Serum concentrations of epiregulin, amphiregulin, betacellulin, TGF-α, fibroblast growth factor 2, placental growth factor (PLGF), and tenascin C were increased in rheumatoid arthritis patients. Furthermore, local blockades of these growth factors suppressed the development of cytokine-induced arthritis in mice by inhibiting chemokine and IL-6 expressions.

Inflammation amplifier, a new paradigm in cancer biology.

Tumor-associated inflammation can induce various molecules expressed from the tumors themselves or surrounding cells to create a microenvironment that potentially promotes cancer development. Inflammation, particularly chronic inflammation, is often linked to cancer development, even though its evolutionary role should impair nonself objects including tumors. The inflammation amplifier, a hyperinducer of chemokines in nonimmune cells, is the principal machinery for inflammation and is activated by the simultaneous stimulation of NF-κB and STAT3.

The diabetes-susceptible gene SLC30A8/ZnT8 regulates hepatic insulin clearance.

Recent genome-wide association studies demonstrated that common variants of solute carrier family 30 member 8 gene (SLC30A8) increase susceptibility to type 2 diabetes. SLC30A8 encodes zinc transporter-8 (ZnT8), which delivers zinc ion from the cytoplasm into insulin granules. Although it is well known that insulin granules contain high amounts of zinc, the physiological role of secreted zinc remains elusive.

Disease-association analysis of an inflammation-related feedback loop.

The IL-6-triggered positive feedback loop for NFκB signaling (or the IL-6 amplifier/Inflammation amplifier) was originally discovered as a synergistic-activation signal that follows IL-17/IL-6 stimulation in nonimmune cells. Subsequent results from animal models have shown that the amplifier is activated by stimulation of NFκB and STAT3 and induces chemokines and inflammation via an NFκB loop. However, its role in human diseases is unclear.

IL-6 amplifier activation in epithelial regions of bronchi after allogeneic lung transplantation.

The IL-6 amplifier, a positive feedback loop for NFκB signaling, which was originally found to be activated by IL-17A and IL-6 stimulation in non-immune cells, is molecularly a simultaneous activator of NFκB and signal transducer and activator of transcription 3 (STAT3), functionally a local chemokine inducer and pathologically a machinery for inflammation development. It has been shown that IL-6 amplifier activation in epithelial cells contributes to rejection responses in a mouse chronic rejection model that develops a bronchiolitis obliterans (BO)-like disease. We investigated whether the IL-6 amplifier is activated in BO regions of a human lung graft after allogeneic transplantation.

The pathological and physiological roles of IL-6 amplifier activation.

The NFκB-triggered positive feedback loop for IL-6 signaling in type 1 collagen+ non-immune cells (IL-6 amplifier) was first discovered to be a synergistic signal that is activated following IL-17A and IL-6 stimulation in type 1 collagen+ non-immune cells. Subsequent disease models have shown that it can also be stimulated by the simultaneous activation of NFκB and STAT3, functions as a local chemokine inducer, and acts as a mechanism for local inflammation, particularly chronic ones like rheumatoid arthritis and a multiple sclerosis. Moreover, we have recently shown that hyper activation of the IL-6 amplifier via regional neural activation establishes a gateway for immune cells including autoreactive T cells to pass the blood-brain barrier at dorsal vessels in 5(th) lumbar cord.

IL-6 amplifier, NF-κB-triggered positive feedback for IL-6 signaling, in grafts is involved in allogeneic rejection responses.

The IL-6-amplifier first was discovered as a synergistic activation mechanism for NF-κB/STAT3 in type 1 collagen(+) cells. This process is marked by the hyperinduction of chemokines and subsequent local inflammation that leads to autoimmune diseases. In this study, we show that IL-6 amplifier activation in grafts plays important roles in allogeneic graft rejection by using a tracheal heterotopic transplantation model that includes bronchiolitis obliterans, a pathological marker for chronic rejection.

A novel role of the L-type calcium channel α1D subunit as a gatekeeper for intracellular zinc signaling: zinc wave.

Recent studies have shown that zinc ion (Zn) can behave as an intracellular signaling molecule. We previously demonstrated that mast cells stimulated through the high-affinity IgE receptor (FcεRI) rapidly release intracellular Zn from the endoplasmic reticulum (ER), and we named this phenomenon the "Zn wave". However, the molecules responsible for releasing Zn and the roles of the Zn wave were elusive.

Regional neural activation defines a gateway for autoreactive T cells to cross the blood-brain barrier.

Although it is believed that neural activation can affect immune responses, very little is known about the neuroimmune interactions involved, especially the regulators of immune traffic across the blood-brain barrier which occurs in neuroimmune diseases such as multiple sclerosis (MS). Using a mouse model of MS, experimental autoimmune encephalomyelitis, we show that autoreactive T cells access the central nervous system via the fifth lumbar spinal cord. This location is defined by IL-6 amplifier-dependent upregulation of the chemokine CCL20 in associated dorsal blood vessels, which in turn depends on gravity-induced activation of sensory neurons by the soleus muscle in the leg.

Biochemical characterization of human ZIP13 protein: a homo-dimerized zinc transporter involved in the spondylocheiro dysplastic Ehlers-Danlos syndrome.

The human SLC39A13 gene encodes ZIP13, a member of the LZT (LIV-1 subfamily of ZIP zinc transporters) family. The ZIP13 protein is important for connective tissue development, and its loss of function is causative for the spondylocheiro dysplastic form of Ehlers-Danlos syndrome. However, this protein has not been characterized in detail.

Zinc homeostasis and signaling in health and diseases: Zinc signaling.

The essential trace element zinc (Zn) is widely required in cellular functions, and abnormal Zn homeostasis causes a variety of health problems that include growth retardation, immunodeficiency, hypogonadism, and neuronal and sensory dysfunctions. Zn homeostasis is regulated through Zn transporters, permeable channels, and metallothioneins. Recent studies highlight Zn's dynamic activity and its role as a signaling mediator.

Gab2, via PI-3K, regulates ARF1 in FcεRI-mediated granule translocation and mast cell degranulation.

Mast cells are major players in allergic responses. IgE-dependent activation through FcεR leads to degranulation and cytokine production, both of which require Gab2. To clarify how the signals diverge at Gab2, we established Gab2 knock-in mice that express Gab2 mutated at either the PI3K or SH2 domain-containing protein tyrosine phosphatase-2 (SHP2) binding sites.