Immunoglobulin G4-related disease is mainly treated with glucocorticoids. In many cases, this disease is resistant to glucocorticoids, and their toxicity can be a problem. We encountered a patient with immunoglobulin G4-related disease affecting multiple organs (such as the skin, lung, and lacrimal gland), who had comorbidities, including atopic dermatitis and diabetes. In this case, while glucocorticoid tapering was difficult, the introduction of upadacitinib resulted in remission of both atopic dermatitis and immunoglobulin G4-related disease without glucocorticoid dose escalation. Peripheral blood flow cytometry analysis showed that the proportions of activated non Th1/Th17 cells subset (Th2 cells), follicular helper T cells, and plasmocytes were increased before upadacitinib therapy but all normalised after treatment. Interleukin-4 and interleukin-21 signals are important for the differentiation of CD4+ T cells into type 2 helper T or B cells in the peripheral blood. Our case suggested that inhibition of Janus kinase 1, which mediates these signals, might have contributed to improved pathological conditions in immunoglobulin G4-related disease.

Because of their ability to induce lymphocyte apoptosis, glucocorticoids (GC) are widely used to treat hematological malignancies such as lymphomas and multiple myeloma. Their effectiveness is often limited, however, due to the development of glucocorticoid resistance by a variety of molecular mechanisms. Here we performed an unbiased genome-wide CRISPR screen with the human T-cell leukemia cell line Jurkat to find previously unidentified genes required for GC-induced apoptosis. One such gene was KMT2D (also known as MLL2 or MLL4), which encodes a histone lysine methyltransferase whose mutations are associated with a variety of cancers, blood malignancies in particular, and are considered markers of poor prognosis. Knockout of KMT2D by CRISPR/Cas9 gene editing in Jurkat and several multiple myeloma cell lines downregulated GR protein expression. Surprisingly, this was not due to a reduction in GR transcripts, but rather to a decrease in the protein\'s half-life, primarily due to proteasomal degradation. Reconstitution of KMT2D expression restored GR levels. In contrast to the known ability of KMT2D to control gene transcription through covalent histone methylation, KMT2D-mediated upregulation of GR levels did not require its methyltransferase activity. Co-immunoprecipitation and proximity ligation assays found constitutive binding of KMT2D to the GR, which was enhanced in the presence of GC. These observations reveal KMT2D to be essential for the stabilization of cellular GR levels, and suggest a possible mechanism by which KMT2D mutations may lead to GC resistance in some malignancies.

Glucocorticoids（GC） are widely used in the clinical treatment of autoimmune inner ear diseases, sudden sensorineural hearing loss, Meniere\'s disease, sinusitis and other otolaryngology diseases. However, GC resistance remains a major factor contributing to the poor efficacy of clinical treatments. The mechanism of GC resistance is still unclear. This paper reviews the related mechanisms of GC resistance from the perspectives of GC receptor factors and non-GC receptor factors. Additionally, it summarizes the latest research progress on GC resistance in otolaryngological diseases, with the aim of identifying effective clinical alternative treatment options for reversing GC resistance in the future.
摘要: 糖皮质激素（glucocorticoids，GC）临床上广泛应用于自身免疫性内耳病、突发性聋、梅尼埃病及鼻窦炎等耳鼻咽喉疾病的治疗，部分患者存在GC抵抗现象，但导致GC抵抗因素机制尚不清楚，本文从GC受体因素和非GC受体因素两方面阐述了GC抵抗的相关机制，并综述其在耳鼻咽喉科疾病的最新研究进展，旨在未来寻找GC抵抗生物标志物，提高GC疗效提出新策略。.

Chronic psychosocial stress induced by the chronic subordinate colony housing (CSC, 19 Days) paradigm promotes functional splenic in vitro glucocorticoid (GC) resistance, but only if associated with significant bite wounding or prior abdominal transmitter implantation. Moreover, sensory contact to social defeat of conspecifics represents a social stressor for the observer individual. As the occurence and severity of bite wounding is not adequately controllable, the present study aimed to develop an animal model, allowing a bite wound-independent, more reliable generation of chronically-stressed mice characterized by functional splenic in vitro GC resistance. Therefore, male C57BL/6N mice received a standardized sterile intraperitoneal (i.p.) incision surgery or SHAM treatment one week prior to 19-days of (i) CSC, (ii) witnessing social defeat during CSC exposure in sensory contact (SENS) or (iii) single-housing for control (SHC), before assessing basal and LPS-induced splenic in vitro cell viability and GC resistance. Our results indicate that individually-housed SENS but not CSC mice develop mild signs of splenic in vitro GC resistance, when undergoing prior i.p.-wounding. Taken together and considering that future studies are warranted, our findings support the hypothesis that the combination of repeated standardized i.p.-wounding with chronic sensory stress exposure represents an adequate tool to induce functional splenic in vitro GC resistance independent of the occurrence of uncontrollable bite wounds required in social stress paradigms to induce a comparable phenotype.

BACKGROUND: Glucocorticoids (GCs) are commonly used as the primary chemotherapy for lymphoid malignancies, including acute lymphoblastic leukemia (ALL). However, the development of GC resistance limits their prolonged use.
METHODS: In this study, we investigated the potential of a newly synthesized indole derivative called LWX-473, in combination with the classic GC Dexamethasone (DEX), to enhance the responsiveness of Jurkat cells to GC treatment.
RESULTS: Our findings demonstrate that LWX-473 alone or in combination with DEX significantly improves GC-induced cell apoptosis and arrests the cell cycle in the G1 phase. Notably, the combination of LWX-473 and DEX exhibits superior efficacy in killing Jurkat cells compared to LWX-473 alone. Importantly, this compound demonstrates reduced toxicity towards normal cells.
CONCLUSIONS: Our study reveals that LWX-473 has the ability to restore the sensitivity of Jurkat cells to DEX by modulating the mitochondrial membrane potential, activating the expression of DEX-liganded glucocorticoid receptor (GR), and inhibiting key molecules in the JAK/STAT signaling pathway. These findings suggest that LWX-473 could be a potential therapeutic agent for overcoming GC resistance in lymphoid malignancies.

BACKGROUND: Increased serum cortisol (COR) concentrations may induce glucocorticoid resistance by down-regulation of glucocorticoid receptor (GCR), resulting in decreased chemotherapy efficacy in dogs with lymphoma.
OBJECTIVE: Investigate the relationship between serum COR concentrations and chemotherapy outcomes in dogs with lymphoma.
METHODS: Thirty client-owned dogs with lymphoma, with serum COR concentration measured using serum samples collected at diagnosis.
METHODS: Retrospective study. Dogs were divided into 2 groups based on serum COR concentrations: a normal group (n = 16) with COR concentrations <6 μg/dL and a high group (14) with COR concentrations ≥6 μg/dL. We compared signalment, clinical signs, stage, type of lymphoma, adrenal gland size, alkaline phosphatase (ALP) activity, response to chemotherapy, progression-free survival (PFS), overall survival (OS), and rate of P-glycoprotein (P-gp)- and GCR-positive cells between the 2 groups.
RESULTS: No significant differences were found in the demographic characteristics between the 2 groups. However, the high COR group exhibited a significantly lower response to chemotherapy, PFS, and OS compared with the normal COR group. Serum ALP activity was significantly higher in the high COR group than in the normal COR group. Adrenal gland size was also significantly larger in the high COR group. Although no significant differences were found in the rate of P-gp-positive cells between the 2 groups, the rate of GCR-positive cells was significantly lower in the high COR group.
CONCLUSIONS: Our data suggests that measurement of serum COR concentrations may serve as a potential prognostic factor and evaluation index.

Depression is a severe mental disorder that disrupts mood and social behavior and is one of the most common neuropsychological symptoms of other somatic diseases. During the study of the disease, a number of theories were put forward (monoamine, inflammatory, vascular theories, etc.), but none of those theories fully explain the pathogenesis of the disease. Steroid resistance is a characteristic feature of depression and can affect not only brain cells but also immune cells. T-helper cells 17 type (Th17) are known for their resistance to the inhibitory effects of glucocorticoids. Unlike the inhibitory effect on other subpopulations of T-helper cells, glucocorticoids can enhance the differentiation of Th17 lymphocytes, their migration to the inflammation, and the production of IL-17A, IL-21, and IL-23 in GC-resistant disease. According to the latest data, in depression, especially the treatment-resistant type, the number of Th17 cells in the blood and the production of IL-17A is increased, which correlates with the severity of the disease. However, there is still a significant gap in knowledge regarding the exact mechanisms by which Th17 cells can influence neuroinflammation in depression. In this review, we discuss the mutual effect of glucocorticoid resistance and Th17 lymphocytes on the pathogenesis of depression.

The normal stress response in humans is governed by the hypothalamic-pituitary-adrenal (HPA) axis through heightened mechanisms during stress, raising blood levels of the glucocorticoid hormone cortisol. Glucocorticoids are quintessential compounds that balance the proper functioning of numerous systems in the mammalian body. They are also generated synthetically and are the preeminent therapy for inflammatory diseases. They act by binding to the nuclear receptor transcription factor glucocorticoid receptor (GR), which has two main isoforms (GRα and GRβ). Our classical understanding of glucocorticoid signaling is from the GRα isoform, which binds the hormone, whereas GRβ has no known ligands. With glucocorticoids being involved in many physiological and cellular processes, even small disruptions in their release via the HPA axis, or changes in GR isoform expression, can have dire ramifications on health. Long-term chronic glucocorticoid therapy can lead to a glucocorticoid-resistant state, and we deliberate how this impacts disease treatment. Chronic glucocorticoid treatment can lead to noticeable side effects such as weight gain, adiposity, diabetes, and others that we discuss in detail. There are sexually dimorphic responses to glucocorticoids, and women tend to have a more hyperresponsive HPA axis than men. This review summarizes our understanding of glucocorticoids and critically analyzes the GR isoforms and their beneficial and deleterious mechanisms and the sexual differences that cause a dichotomy in responses. We also discuss the future of glucocorticoid therapy and propose a new concept of dual GR isoform agonist and postulate why activating both isoforms may prevent glucocorticoid resistance.

Glucocorticoids have been widely used in the treatment of ulcerative colitis, but not all patients benefit from this therapy due to hormone resistance. Mir-150-5p has been reported to enhance the efficacy of glucocorticoids, and low serum mir-150-5p expression has been linked to glucocorticoid resistance in ulcerative colitis patients. The aim of this study was to elucidate the mechanisms of mir-150-5p regulation on glucocorticoid resistance. An ulcerative colitis mouse model was used to evaluate changes in ulcerative colitis symptoms, inflammatory factors, and glucocorticoid resistance-related gene expression. The results showed that mir-150-5p suppression with antagomirs did not significantly interfere with or enhance the induction of ulcerative colitis symptoms by dextran sulfate sodium, but it did attenuate the inflammation inhibitory effect of dexamethasone by abnormally regulating the expression of IL-17a, IL-10, IL-2 and IL-6 levels and myeloperoxidase activity. Mir-150-5p inhibition also induced a glucocorticoid-resistant gene expression profile in colon tissues of ulcerative colitis mice, with upregulation of p-ERK, p-JNK, and HSP90 and downregulation of p-GRa, FKBP4, and HDAC2 expression. Our results indicate that mir-150-5p suppression attenuates the anti-inflammatory effect of glucocorticoids and may function as a driver element in ulcerative colitis glucocorticoid resistance. AVAILABILITY OF DATA AND MATERIALS: All data and figures analyzed in this study are available from the corresponding author by request.

Chronic psychosocial stress is a burden of modern society and poses a clear risk factor for a plethora of somatic and affective disorders, of which most are associated with an activated immune status and chronic low-grade inflammation. Preclinical and clinical studies further suggest that a failure in immunoregulation promotes an over-reaction of the inflammatory stress response and, thus, predisposes an individual to the development of stress-related disorders. Therefore, all genetic (i.e., sex) and environmental (i.e., early life adversity; ELA) factors facilitating an adult\'s inflammatory stress response are likely to increase their stress vulnerability. In the present study we investigated whether repeated subcutaneous (s.c.) administrations with a heat-killed preparation of Mycobacterium vaccae (M. vaccae; National Collection of Type Cultures (NCTC) 11659), an abundant soil saprophyte with immunoregulatory properties, are protective against negative behavioral, immunological and physiological consequences of ELA alone or of ELA followed by chronic psychosocial stress during adulthood (CAS) in male and female mice. ELA was induced by the maternal separation (MS) paradigm, CAS was induced by 19 days of chronic subordinate colony housing (CSC) in males and by a 7-week exposure to the social instability paradigm (SIP) in females. Our data indicate that ELA effects in both sexes, although relatively mild, were to a great extent prevented by subsequent s.c. M. vaccae administrations. Moreover, although the use of different paradigms for males and females impedes a direct comparison, male mice seemed to be more susceptible to CAS than females, with only females benefitting slightly from the stress protective effects of s.c. M. vaccae administrations when given prior to CAS alone. Finally, our data support the hypothesis that female mice are more vulnerable to the additive effects of ELA and CAS than male mice and that s.c. M. vaccae administrations subsequent to ELA but prior to CAS are protective in both sexes. Taken together and considering the limitation that CAS in males and females was induced by different paradigms, our findings are consistent with the hypotheses that murine stress vulnerability during different phases of life is strongly sex dependent and that developing immunoregulatory approaches, such as repeated s.c. administrations with immunoregulatory microorganisms, have potential for prevention/treatment of stress-related disorders.