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摘要： Resistance to cyclin-dependent kinase 4/6 (CDK4/CDK6) inhibitors leads to treatment failure and disease progression in women with hormone receptor+HER2- (HR+HER2-) breast cancer (BC). We delineated a hypoxia-sensitive, CCL2-dependent pathway recruiting interleukin-17A (IL-17A)-secreting gamma delta T cells to mouse HR+HER2- BCs following CDK4/CDK6 inhibition, resulting in repolarization of tumor-associated macrophages (TAMs) toward an immunosuppressive CX3CR1+ phenotype associated with resistance. Increased IL-17A signaling and intratumoral gamma delta T cell abundance positively correlated with advanced grade and/or reduced survival in two cohorts of individuals with HR+HER2- BC. Circulating gamma delta T cells and plasma CCL2 levels negatively correlated with progression in an independent series of individuals with HR+HER2- BC receiving CDK4/CDK6 inhibitors. Intratumoral gamma delta T cells were increased in post- versus pretreatment biopsies from individuals with HR+HER2- BC relapsing on CDK4/CDK6 inhibitors. CX3CR1+ TAMs had negative prognostic impact in women with HR+HER2- BC receiving neoadjuvant PD-1 blockage and radiotherapy. Thus, gamma delta T cells and CX3XR1+ TAMs may favor resistance to CDK4/CDK6 inhibitors in individuals with HR+HER2- BC.

关键词： 类风湿关节炎   间质性肺病   风湿肺痹方   TNF-Tg小鼠   巨噬细胞极化  

摘要： 背景类风湿关节炎合并间质性肺疾病（RA-ILD）是类风湿关节炎（RA）的常见并发症，20%～50%的RA患者会继发ILD，使RA患者死亡风险增加。目前临床缺乏安全有效、靶向明确的治疗RA-ILD药物。中医药在RA-ILD治疗中具有一定优势，风湿肺痹方作为常用方剂，其疗效确切，但作用机制尚不明确，需通过实验研究加以验证。目的 探讨FSFBF对肿瘤坏死因子α转基因（TNF-Tg）小鼠RA-ILD的疗效和作用机制。方法 于2024年3月—2025年1月，采用雌性TNF-Tg小鼠作为RA-ILD模型小鼠，将24只2.5月龄TNF-Tg小鼠随机分为模型组（TNF-Tg组）、FSFBF低剂量组（Low组）、FSFBF中剂量组（Middle组）、FSFBF高剂量组（High组），同时随机挑选6只同窝野生型小鼠作为对照组（WT组）。TNF-Tg组给予生理盐水，Low、Middle、High组分别给予5.825、13.65、27.3g·kg-1·d-1FSFBF灌胃。9周后采集小鼠体质量、踝关节临床评分和前肢抓力数据；取踝关节与肺脏组织进行HE染色、Masson染色、番红固绿染色；使用酶联免疫吸附试验（ELISA）检测小鼠血清炎症因子含量；采用免疫荧光染色标记肺脏巨噬细胞；采用实时荧光定量PCR（RT-qPCR）检测肺脏炎症因子m RNA相对表达量。结果 4.5月龄时，TNFTg组体质量低于WT组，Low组、High组高于TNF-Tg组（P<0.05）;TNF-Tg组踝关节临床评分高于WT组，Middle组、High组低于TNF-Tg组（P<0.05）;TNF-Tg组前肢抓力低于WT组，High组高于TNF-Tg组（P<0.05）。病理结果显示：TNF-Tg组踝关节炎症面积、肺脏炎症面积、肺脏I型胶原纤维面积大于WT组，Middle组和High组踝关节炎症面积小于TNF-Tg组，Middle组关节软骨面积大于TNF-Tg组，Low组、Middle组和High组肺脏炎症与肺脏I型胶原纤维面积小于TNF-Tg组（P<0.05）。免疫荧光染色结果显示：TNF-Tg组肺脏M1、M2型巨噬细胞数量大于WT组，Low组、Middle组和High组M1型巨噬细胞数量低于TNF-Tg组，M2型巨噬细胞数量高于TNF-Tg组（P<0.05）。ELISA结果显示：TNF-Tg组血清TNF-α、IL-1β和IL-6水平高于WT组，Low组、Middle组、High组血清TNF-α和IL-1β水平低于TNF-Tg组，High组血清IL-6水平低于TNF-Tg组（P<0.05）。RT-qPCR结果显示：TNF-Tg组小鼠肺脏TNF-α和IL-1β相对表达量高于WT组，High组低于TNF-Tg组（P<0.05）;Middle组和High组肺脏IL-1相对表达量低于TNF-Tg组（P<0.05）;TNF-Tg组小鼠踝关节TNF-α和IL-1β相对表达量高于WT组，Low组、Middle组和High组低于TNF-Tg组（P<0.05）。结论 FSFBF通过调节肺脏巨噬细胞极化，改善TNF-Tg小鼠RA-ILD的症状，减轻关节炎症、软骨破坏、肺脏炎症和肺泡纤维化，FSFBF可能成为临床治疗RA-ILD的新方法。

摘要： Kumar A, Bhoopathi P, Mannangatti P, et al. Novel fusion superkine, IL-24S/IL-15, enhances immunotherapy of brain cancer. J Immunother Cancer 2025;13:e011198.

关键词： pancreatic injury   pancreatic fibrosis   trNK cells   IL-6   IL-6R   MASH  

摘要： Background and aim: Metabolic-associated steatohepatitis (MASH) and pancreatic inflammation are key complications of obesity-related metabolic syndrome. Elevated IL-6;a proinflammatory cytokine, contributes to liver steatosis and pancreatic beta-islet cells dysfunction. This study explores pancreatic tissue-resident (tr)NK cells IL-6 receptor (IL-6R) in pancreatic injury in a murine MASH model. Methodology: MASH models were established using male Ob/Ob mice fed a high-fat diet (Ob/Ob(HFD);60.3% kcal from fat) for 4 weeks and using immunocompromised NOD-SCID IL2r gamma null (NSG) mice fed with HFD for 16 weeks and i.v. injected with 10 x 10(6) pancreatic trNK and treated with IL-6R antagonizing antibody on week 12. Biochemical assays assessed serum ALT, AST, lipids, glucose, and insulin levels. Pancreatic injury was analyzed through mRNA expression of Reg1, Reg3, oxidative stress marker of tissue malondialdehyde (MDA) and beta-islet cells' proliferation and apoptosis. Fibrotic markers of alpha-SMA, Collagen-I, and Fibronectin were assessed via RT-PCR and trNK cell activation (CD107a, NKp46, IFN-gamma) were assessed by flow cytometry. Results: Ob/Ob(HFD) mice exhibited increased serum cholesterol, triglycerides, fasting blood glucose, and liver injury enzymes. Markers of pancreatic injury of Reg1/Reg3 and pancreatic MDA with beta-islet cells apoptosis were significantly elevated compared to littermates' control. These results were accompanied by a decline in trNK counts and activations (P < 0.05). In an adoptive transfer model, NSG mice fed with HFD and transplanted with trNK cells from Ob/Ob(HFD) donors (expressing high IL-6) exhibited similar pancreatic injury markers, whereas those receiving trNK cells from Ob/Ob(HFD) mice pre-treated with an IL-6R antagonist showed marked reductions in Reg1/Reg3 (similar to 2-fold), MDA (similar to 1.77-fold), and beta-islet cells apoptosis (similar to 2.2-fold). Moreover, phenotypic characterization of the NSG mice fed an HFD tra

关键词： IL-6   IAV   innate immunity   inflammation   cytokine storm  

摘要： Interleukin-6 (IL-6), a pleiotropic cytokine, is induced by infection of influenza A virus (IAV), where it plays a pivotal role in immune defense and the regulation of inflammation. IAV induces IL-6 transcription upon recognition by pattern recognition receptors, which activate downstream signaling cascades, leading to the activation of transcription factors. Activated transcription factors subsequently regulate the expression of IL-6 in innate immune cells, such as macrophages, dendritic cells, and epithelial cells. IL-6 contributes to antiviral immunity by promoting the recruitment of immune cells to sites of infection and amplifying the inflammatory response. While optimal IL-6 production is essential for effective anti-IAV immunity, excessive IL-6 production can contribute to a dysregulated immune response, leading to a cytokine storm. In this context, IL-6 signaling, in coordination with other proinflammatory cytokines such as TNF-alpha and IL-1 beta, not only enhances its own production but can also serve as a key mediator of inflammation. This cascade can result in exaggerated immune responses, causing tissue damage and potentially leading to severe outcomes, including organ failure and death. Understanding the molecular mechanisms underlying cytokine storms presents important therapeutic opportunities. However, the precise pathways responsible for excessive IL-6 production and its dysregulation during IAV infection is not fully understood. This review explores the reported mechanisms regulating IL-6 induction in response to IAV and its innate immune role in IAV pathogenesis, highlighting existing research gaps in understanding IAV-induced IL-6 production and its impact on immune modulation. A deeper understanding of IAV-induced IL-6 production and signaling could inform the development of targeted therapies to more effectively manage influenza.

关键词： Brucea javanica   Luteolin   Multiple myeloma   TNF/NF-kappa B signaling pathway   Network pharmacology   Traditional Chinese medicine  

摘要： This study aims to explore the pharmacological mechanism of Brucea javanica (BJ) in treating multiple myeloma (MM) through network pharmacology and validate this mechanism via in vitro experiments. Active pharmaceutical ingredients (APIs) of BJ and their potential targets were identified, along with MM-related targets. By plotting protein-protein interaction (PPI) networks, hub genes responsible for BJ in treating MM were identified and subjected to molecular docking. In MM cell lines H929 and U266, regulatory effects of BJ and luteolin (the major compound of BJ) on the behaviors of MM cells were examined. BJ extract exhibited dose-dependent cytotoxicity against MM cells, with IC50 values of 5.03 mu L/mL (48 h) for H929, and 1.06 mu L/mL (48 h) for U266. Network pharmacology identified 14 APIs and 11 hub genes, with molecular docking confirming strong binding affinity between luteolin and TNF (-8.001 kcal/mol). 48-hour luteolin treatment suppressed MM cell proliferation (IC50: 84.73 mu M for H929;46.93 mu M for U266), induced apoptosis (up to 53.03% and 9.22% late apoptosis in H929 and U266 at 80 mu M), and arrested cell cycle at G0/G1 phase. It downregulated TNF/NF-kappa B pathway components, reducing mRNA levels of TNF, IL-6, and NFKB1, and protein levels of p105, p50, and p65. TNF-alpha secretion decreased in luteolin-treated cells to 10.62% in H929 cells and 67.25% in U266 cells. This study demonstrates that BJ inhibits MM progression primarily via suppression of the TNF/NF-kappa B signaling pathway, with luteolin as a pivotal bioactive compound.

关键词： Human hepatic stellate cells   LX-2   MDA-7/IL-24   RGD peptide   Inflammation  

摘要： Hepatic stellate cells (HSCs) serve as pivotal mediators of liver fibrogenesis. This study investigates the pro-inflammatory effects of melanoma differentiation-associated gene-7/interleukin-24 (MDA-7/IL-24) within both murine and cellular models. By employing the hydrodynamic injection of a plasmid expressing IL-24/mda7 (PMDA-7) in mice, significant inflammatory histopathological alterations were observed in the liver tissue. In human LX-2 HSCs, treatment with recombinant IL-24 (rIL-24), as well as transfection with PMDA-7 or RGD-modified PMDA-7-RGD plasmids, resulted in an increased expression of pro-inflammatory cytokines (IL-1 beta, IL-6, IL-17, IL-18, IL-23) and regulatory molecules (SOCS1, SOCS3). Importantly, the RGD-modified variant exhibited the most pronounced effects, with PMDA-7-RGD inducing the highest levels of IL-1 beta, IL-6, IL-17, and IL-18 expression, whereas rIL-24 was noted to most effectively upregulate IL-23 (P < 0.05). These findings substantiate that MDA-7/IL-24 exerts pro-inflammatory effects on HSCs, which are further amplified by RGD conjugation, thus suggesting its potential involvement in the pathogenesis of liver inflammation and fibrosis.

关键词： primary sclerosing cholangitis   PSC   fibrosis   Mapkap2   MK2   IL-22  

摘要： Primary sclerosing cholangitis (PSC) is a chronic liver disease characterized by bile duct inflammation and fibrosis, leading to cirrhosis and liver failure. Current therapies are limited to symptom management, with no approved treatments targeting fibrosis. We have identified the MAP kinase-activated protein kinase 2 (MK2) pathway as a potential therapeutic target for treating PSC due to its role in promoting inflammatory cytokine production and activation of fibroblasts. Thus, MDR2 knockout mice were treated therapeutically with MK2 inhibitors, which led to significantly reduced hepatic inflammation and fibrosis. Liver enzymes, collagen 1A1, and fibronectin were decreased in serum with MK2 inhibitor treatment. Furthermore, the production of IL-6, TNF alpha, CXCL5, collagen 1A1, and fibronectin was decreased in liver tissues and liver stellate cells, whereas the production of IL-10, G-CSF, and IL-22 was increased. MDR2KO mice treated with IL-22 also showed improvements in inflammation and fibrosis, along with increased IL-10 and G-CSF production. Taken together, we identified both a direct mechanism of MK2 regulation of fibrotic factors and an indirect cytokine-mediated mechanism whereby the levels of IL-22, IL-10, and G-CSF were increased with MK2 inhibition and contributed to decreased levels of fibrotic factors. These data suggest that the MK2 pathway is a promising treatment target for PSC.

摘要： Objectives Systemic lupus erythematosus (SLE) is a complex autoimmune disease strongly associated with the major histocompatibility complex (MHC) region, but precisely pinpointing the risk variants remains challenging. This study aimed to comprehensively profile SLE-driving variants using a newly developed East Asian MHC imputation reference panel, capable of simultaneously imputing diverse MHC variants, including multilevel human leukocyte antigen (HLA) variants and copy number variations (CNVs) of C4 elements, such as C4A, C4B, and human endogenous retrovirus (HERV). Methods Using the whole-genome-sequencing (WGS) data from ∼2000 Korean samples, we genotyped and phased MHC variants, including HLA variants and C4 -related CNVs, to construct an MHC reference panel. Imputation performance of the panel was assessed through leave-one-out cross-validation and validated using WGS and droplet digital polymerase chain reaction methodology. The panel was applied to 2 independent SLE genome-wide association study datasets, followed by stepwise conditional analyses, fine-mapping, and model comparisons. Results The MHC panel achieved high imputation accuracies of 95% for HLA and 94% for C4 at the haploid-level. Independent contributions to SLE risk were identified from 6 amino acid positions altering the epitope-binding surfaces of HLA-DRB1 and HLA-C. Reduced C4A copy numbers and increased HERV copy numbers, collectively lowering C4 protein levels, were associated with increased SLE risk, independent of HLA variants. Our refined MHC-SLE association model provided superior explanations for SLE risk over previous association models in an independent Korean population. Conclusions This study enhanced the understanding of HLA and C4 in SLE pathogenesis and holds promise for advancing MHC association studies for immune-mediated inflammatory disorders in East Asians using our MHC panel, accessible via https://***/usab/kis/*** .