Higher Serum IL-6 Research Articles

Cytokine correlations in childhood-onset rheumatic diseases with pulmonary involvement.

There was less research about cytokines in lung involvement of childhood-onset rheumatic diseases (RD) patients. In this investigation, blood levels of 12 cytokines were tested in order to explore their associations with lung involvement in newly diagnosed childhood-onset RD patients. High-resolution computed tomography (HRCT) and pulmonary function tests (PFTs) were performed on 53 newly diagnosed RD patients without any treatment in our department between July 2021 and December 2023. Patients were separated into groups based on whether their lungs were involved or not according to abnormalities found on HRCT or PFTs. We examined the serum cytokines with 41 healthy, age and gender-matched controls. The majority of serum cytokine levels were statistically different between the RD group with lung involvement and the control group. The RD group with lung involvement had considerably higher serum IL-6 and IFN-γ levels than the RD group without lung involvement or control group. The median serum IL-6 levels were 19 pg/ml [interquartile range (IQR) 6.9, 27.6], 4.4 pg/ml (IQR 2.0, 10.5), and 2.0 pg/ml (IQR 2.0, 2.0) in RD group with lung involvement, RD group without lung involvement, and control group, respectively. Similarly, the median serum IFN-γ levels were 6.0 pg/ml (IQR 5.0, 15), 5.0 pg/ml (IQR 5.0, 5.0), and 5.0 pg/ml (IQR 5.0, 5.0) in RD group with lung involvement, RD group without lung involvement, and control group, respectively. The receiver operating characteristic (ROC) curve study showed that IL-6 and IFN-γ had area under the curve (AUC) values of 0.782 and 0.742, respectively, indicating their significant diagnostic potential for lung involvement in RD patients. Our findings imply that IL-6 and IFN-γ may be associated with the development of lung illnesses and may be involved in the pathophysiology of RD. Thus, in individuals with RD, elevated levels of IFN-γ over 5.42 pg/ml or IL-6 above 6.25 pg/ml may warrant suspicion of lung involvement.

Dysregulation of neutrophil extracellular traps (NETs)-related genes in the pathogenesis of diabetic kidney disease - Results from bioinformatics analysis and translational studies

The role of Neutrophil extracellular traps (NETs) in the immunopathogenesis of Diabetic Kidney Disease (DKD) remains elusive. We used a machine learning approach to identify differentially expressed genes (DEGs) associated with NETs in human DKD kidney biopsy datasets and validated the results using single-nucleus RNA sequencing datasets. The expressions of these candidate genes and related cytokines were verified in blood obtained from DKD patients. Three NETs-associated genes (ITGAM, ITGB2 and TLR7) were identified, which all showed significant upregulation in both glomerular and tubulointerstitial compartments in human DKD kidneys. DKD patients showed significantly higher number of activated neutrophils with increased ITGAM and ITGB2 expression, higher serum IL-6 but lower IL-10, compared to healthy controls (p all <0.01). This study suggests that dysregulation of NETs-associated genes ITGAM and ITGB2 are related to the pathogenesis of DKD, and may serve as novel diagnostic markers and therapeutic targets in DKD.

Long-term efficacy of MAS825, a bispecific anti-IL1β and IL-18 monoclonal antibody, in two patients with sJIA and recurrent episodes of MAS.

Systemic juvenile idiopathic arthritis (sJIA), a multifaceted autoinflammatory disorder, can be complicated by life-threatening conditions such as macrophage activation syndrome (MAS) and interstitial lung disease (ILD). The management of these conditions presents a therapeutic challenge, underscoring the need for innovative treatment approaches. to report the possible role of MAS825, a bispecific anti-IL1β and IL-18 monoclonal antibody, in the treatment of multi-drug-resistant sJIA. We report two patients affected by sJIA with severe and refractory MAS and high serum IL-18 levels, responding to dual blockade of IL-1β and IL-18. The first patient is a 20-year-old man, presenting a severe MAS complicated by thrombotic microangiopathy, following SARS-CoV-2 infection. He was treated with MAS825, with quick improvement. Eighteen months later, the patient is still undergoing biweekly treatment with MAS825, associated with MTX, ciclosporin and low-dose glucocorticoids, maintaining good control over the systemic features of the disease.The second patient, a 10-year-old girl, presented a severe MAS case, complicated by posterior reversible encephalopathy syndrome (PRES), following an otomastoiditis. The MAS was not fully controlled despite treatment with IV high-dose glucocorticoids, anakinra and ciclosporin. She began biweekly MAS825, which led to a prompt amelioration of MAS parameters. After 10 months, the patient continues to receive MAS825 and is in complete remission. In light of the pivotal role of IL-1β and IL-18 in sJIA, MAS and ILD, MAS825 might represent a possible valid and safe option in the treatment of drug-resistant sJIA, especially in the presence of high serum IL-18 levels.

Predictors of exacerbation in Japanese patients with severe asthma: Analysis of the severe asthma research program (Okayama-SARP) cohort

BackgroundBecause exacerbation of severe asthma decreases patients’ quality of life, this study aimed to identify predictive factors for asthma exacerbation. MethodsJapanese patients with severe asthma requiring treatment according to the Global Initiative for Asthma (GINA) guidelines ≥ Step 4 between January 2018 and August 2021 were prospectively enrolled and followed up for one year at facilities participating in the Okayama Respiratory Disease Study Group (Okayama Severe Asthma Research Program). ResultsA total of 85 patients (29 men and 56 women) were included. The median age was 64 (interquartile range [IQR], 51–72) years. Treatment according to GINA Steps 4 and 5 was required in 29 and 56 patients, respectively, and 44 patients (51.8%) were treated with biologics. The median peripheral-blood eosinophil count, fractional exhaled nitric oxide, IgE level, and percent predicted FEV1 (%FEV1) at enrollment were 204 (IQR, 49–436)/μL, 28 (IQR, 15–43) ppb, 172 (IQR, 56–473) IU/mL, and 80.0 (IQR, 61.1–96.1) %, respectively. Exacerbation during the previous year, asthma control test (ACT) score <20, %FEV1 <60%, and serum IL-10 level >6.7 pg/mL were associated with exacerbation during the observation period. ConclusionsExacerbation during the previous year, low ACT score, and low %FEV1 were predictive factors of future exacerbation, even in a cohort with >50% of patients treated with biologics. Furthermore, high serum IL-10 levels might be a new predictive factor.

Association of high disease activity and serum IL-6 levels with the incidence of inflammatory major organ events in Behçet disease: a prospective registry study.

Little is known about the relationship between the disease activity of Behçet disease (BD) and the incidence of inflammatory major organ events. In this prospective registry study, we investigated the association between the Behçet Disease Current Activity Form (BDCAF) and incidence of inflammatory major organ events, defined as the inflammation of the ocular, central nervous, intestinal, and vascular systems in BD. We enrolled participants from Japanese multicenter prospective cohorts. The BDCAF was evaluated annually. BD-related symptoms, including inflammatory major organ events, were monitored. The association between BDCAF and inflammatory major organ events was analyzed by time-to-event analysis. An unsupervised clustering of the participants' BDCAF, therapeutic agents, and multiple serum cytokines was also performed to examine their association with inflammatory major organ events. A total of 260 patients were included. The patients had a median BDCAF score of 2 [Interquartile range, 1-3] at the enrolment and remained disease active at 1- and 2-year follow-ups, indicating residual disease activity in BD. Patients with a BDCAF score of 0 had a longer inflammatory major organ event-free survival at 52 weeks than those with a score of 1 or higher (p=2.2 x 10-4). Clustering analysis revealed that patients who did not achieve remission despite treatment with tumor necrosis factor inhibitors had high serum inflammatory cytokine levels and incidences of inflammatory major organ events. Among the elevated cytokines, IL-6 was associated with inflammatory major organ events. This study suggests that treatment strategies targeting overall disease activity and monitoring residual serum IL-6 may help prevent inflammatory major organ events in BD.

Mesenchymal Stem Cells and Curcumin Effectively Mitigate Freund's Adjuvant- induced Arthritis via their Anti-inflammatory and Gene Expression of COX-1, IL-6 and IL-4.

Rheumatoid arthritis (RA) is a type of arthritis that damages joints and can affect the thymus and the spleen. RA is an autoimmune disorder in which the immune system targets the body's own tissues. The causes of RA are unknown, although a genetic link is thought to be involved. The objective of this research was to evaluate the effect of curcumin, mesenchymal stem cells (MSCs), and their combination on the disruption of serum cytokines, ankle joint, thymus and spleen histopathology, and affected genes in complete Freund's adjuvant (CFA)-induced arthritis in male and female Wistar rats. Experimental animals were organized into 16 groups (6 animals for each), eight groups including male rats and the other eight groups including females rats. The groups are normal control, CMC, curcumin, MSCs, CFA, CFA/curcumin, CFA/ MSCs and the arthritic group treated with MSCs and curcumin. One subcutaneous injection of 0.1 mL CFA was given to rats into the right hind leg footpad to induce RA. The arthritic rats were intravenously injected three times with bone marrow-derived MSCs (BM-MSCs) and/or treated orally with curcumin daily (100 mg per kg body weight per day) for 21 days. Curcumin and BM-MSCs work together to dramatically (P < 0.05) restore the high serum PGE2 and IL-17 levels and lower the IL-13 level in arthritic rats to normal levels. Deleterious effects on the spleen and thymus histological structure were counteracted. Gene expression of COX-1 and IL-6 was increased and IL-4 was decreased; these changes were improved by the combination treatment (P < 0.05). Based on these findings, additive therapeutic effects on RA occur from the combined treatment of curcumin and BM-MSCs compared with their individual use (P < 0.05). Thus, it can be said that both curcumin and BM-MSCs are effective at reducing inflammation while also having beneficial effects on the ankle joint, thymus and spleen.

Higher Serum IL-8 is associated with Reduced PFS and OS during Systemic Therapy in Metastatic Breast, Pancreatic and Prostate Cancer: A Retrospective Study in Patients from BOLERO-2 Trial, Pancreatic and Prostate Cancer Cohorts

Higher Serum IL-8 is associated with Reduced PFS and OS during Systemic Therapy in Metastatic Breast, Pancreatic and Prostate Cancer: A Retrospective Study in Patients from BOLERO-2 Trial, Pancreatic and Prostate Cancer Cohorts

Abstract 627: IL-6 signaling via JAK/STAT axis influences PIM1 expression in renal cell carcinoma

Abstract Renal cell carcinoma (RCC) is a top ten malignancy in the U.S. Overexpression of the proviral integration site for moloney murine leukemia virus 1 (PIM1) kinase is associated with poor clinical outcomes in RCC patients. PIM1 is a constitutively active serine/threonine kinase promoting cell proliferation, apoptosis resistance, invasion, and migration. The mechanisms underlying PIM1 expression and its function in RCC are not fully delineated. IL-6 is a pleiotropic cytokine that activates the JAK/STAT signaling cascade. High serum IL-6 levels are associated with the poor prognosis of RCC patients and may contribute to RCC invasion and metastasis. STAT3/5 binds directly to the PIM1 promoter inducing PIM1 expression. An IL-6/STAT3/PIM1 axis exists in pancreatic and breast cancer. We previously reported that PIM1 is overexpressed in a panel of human RCC cell lines relative to normal and immortalized renal proximal tubule epithelial cells. We also identified that RCC cells secrete IL-6. Our prior studies suggest that differential expression of PIM1 may be linked to autocrine IL-6 signaling. We thus hypothesize that an IL-6/JAK/STAT pathway regulates the expression of PIM1 in RCC. To understand how IL-6 signaling through the JAK/STAT pathway may regulate PIM1 expression in RCC cells, we examined whether IL-6 blockade using anti-IL-6 antibody or tocilizumab, would modulate PIM1 expression. Similarly, we assessed whether ruxolitinib, and LLL12, a STAT3 inhibitor could regulate PIM1 expression. We then evaluated the effect of ruxolitinib treatment on cell viability. In RCC cell lines, IL-6 blockade through either anti-IL-6 antibody or tocilizumab was sufficient to decrease PIM1 protein levels. Treatment with ruxolitinib leads to a dose and time-dependent decrease in PIM1 levels. Incubation with a STAT3 inhibitor also resulted in decreased PIM1 levels in RCC cells. Treatment with ruxolitinib also appears to decrease cell viability in a dose-dependent manner. These results suggest that differential expression of PIM1 in RCC may be linked to autocrine IL-6 signaling via a JAK/STAT/PIM1 axis. Multiple FDA-approved agents are available that target this pathway. Further investigation is required to determine the efficacy of these agents in pre-clinical models and even clinical trials. Citation Format: Kimberly S. Meza, Kimberly Seymour, Sheldon L. Holder. IL-6 signaling via JAK/STAT axis influences PIM1 expression in renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 627.

Abstract B025: IL6 signaling in pre-malignant obese endometrium and endometrial cancer

Abstract Objective: Obesity associated chronic inflammatory status plays a role in the increased endometrial cancer incidences, IL-6 is one of those inflammatory molecules. To explore the potential of targeting pro-inflammation factors for endometrial cancer prevention, using multi-platform and multi-model analysis, we investigated IL6 and its associated signaling in pre-malignant endometrium and low-grade endometrial cancer. Methods: Illumina microarray and Nanostring nCounter® Pancancer Immune profiling panel gene expression profiling was performed on pre-malignant obese endometrium from diet induced obese Wistar rats, and endometrium from obese patients, lean endometrium was used as control. Clariom D assay was performed on RNA extracted from the gland and stroma of human obese endometrial carcinoma (OEC) and obese normal endometrium (ONE). IPA, nSolver, Transcriptome Analysis Console (TAC), and CIBERSORTx were used for data analysis. Ishikawa cells were 2D and 3D cultured, or 3D co-cultured with endometrial stroma cell line SHT290. Western blot was used for testing cell signal activity. Results: Pronounced IL-6 signaling (Z-score:2.3333, p=2.48E-02) was shown in pre-malignant obese endometrium of diet induced obese rats compared with lean littermates: NF-kB signaling (Z-score:2.714, p=3.47E-02), STAT3 signaling (Z-score:2.53, p=6.56E-04), and tumor microenvironment pathway (Z-score: 3.441, p=6.81E-05) were enhanced; PTEN signaling (Z-score:-1.997, p=2.76E-03) was attenuated. IL6R (FC=1.64, p=0.017), MMP2 (FC=1.938, p=0.026), IL1R2 (FC=1.75, p&amp;lt;0.0001), and CCL2 (FC=2.251, p=0.002) expression were increased. IL6 induced stronger STAT3 signaling, and weaker activation of MAPK signaling in Ishikawa cells 3D co-cultured with stroma cells, compared with 3D cultured Ishikawa cells without stroma cells. No IL-6 induced activation of MAPK signaling was observed with activation of Stat3 signaling in 2D-cultured Ishikawa cells. In pre-malignant obese endometrium from patients with high serum IL-6 levels, attenuated pro-inflammation signaling was seen compared with that from patients with low serum IL6 level: expression of IL1A (FC=-2.21, p=0.001), IRF8 (FC=-1.83, p=0.012), GAGE1 (FC=-3.49, p=0.028), and LBP (FC=-2.03, p=0.038) were decreased. Compared with pre-malignant obese endometrium, more regulatory T cell (Tregs, 0.1276 vs 0.077, p=0.04), and less eosinophils (0.003 vs 0.022, p=0.028) in the stroma, and more neutrophils (0.0145 vs. 0, p=0.02) in the tumor glands were observed in obese EC, implicating immuno-suppression in OEC. Conclusion: Due to the elevated systemic pro-inflammation status, pre-malignant obese endometrium demonstrated activated IL-6 signaling. IL-6 induced cell signaling varied by cellular microenvironment. In pre-malignant endometrium from obese women with high systemic IL-6 level, attenuated inflammation signaling was observed compared to those with low serum IL6 levels. Immuno-suppression was implicated in obese EC. Citation Format: Qian Zhang, Brenda Melendez, Xiaoping Su, Mikayla Bowen, Joseph Celestino, Melinda Sue Yates, Karen Lu. IL6 signaling in pre-malignant obese endometrium and endometrial cancer [abstract]. In: Proceedings of the AACR Special Conference on Endometrial Cancer: Transforming Care through Science; 2023 Nov 16-18; Boston, Massachusetts. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(5_Suppl):Abstract nr B025.

An IL-10/DEL-1 axis supports granulopoiesis and survival from sepsis in early life

The limited reserves of neutrophils are implicated in the susceptibility to infection in neonates, however the regulation of neutrophil kinetics in infections in early life remains poorly understood. Here we show that the developmental endothelial locus (DEL-1) is elevated in neonates and is critical for survival from neonatal polymicrobial sepsis, by supporting emergency granulopoiesis. Septic DEL-1 deficient neonate mice display low numbers of myeloid-biased multipotent and granulocyte-macrophage progenitors in the bone marrow, resulting in neutropenia, exaggerated bacteremia, and increased mortality; defects that are rescued by DEL-1 administration. A high IL-10/IL-17A ratio, observed in newborn sepsis, sustains tissue DEL-1 expression, as IL-10 upregulates while IL-17 downregulates DEL-1. Consistently, serum DEL-1 and blood neutrophils are elevated in septic adult and neonate patients with high serum IL-10/IL-17A ratio, and mortality is lower in septic patients with high serum DEL-1. Therefore, IL-10/DEL-1 axis supports emergency granulopoiesis, prevents neutropenia and promotes sepsis survival in early life.

Higher Serum IL-6 and IFN-γ Are Associated with Increased Seroconversion Rate Against SARS-CoV-2 Spike Protein Either After Vaccination or SARS-CoV-2 Infection

Higher Serum IL-6 and IFN-γ Are Associated with Increased Seroconversion Rate Against SARS-CoV-2 Spike Protein Either After Vaccination or SARS-CoV-2 Infection

Autoimmune Limbic Encephalitis in Patients with Hematologic Malignancies after Haploidentical Hematopoietic Stem Cell Transplantation with Post-Transplant Cyclophosphamide.

Autoimmune limbic encephalitis (LE) is a rare, but devastating complication of allogeneic hematopoietic stem cell transplantation (HSCT). There is currently limited evidence describing the risk factors, laboratory features, and underlying mechanisms of this neurologic adverse event. We retrospectively reviewed available clinical, imaging, and laboratory data from adult patients with hematological malignancies who underwent haploidentical HSCT with post-transplant cyclophosphamide (PTCy) at Chungnam National University Hospital from June 2016 to May 2020. Patients who developed LE were compared to those who did not based on clinical assessment, serum inflammatory biomarkers, and reconstitution of various T cell populations. Of 35 patients, 4 developed LE. There were no differences in patient demographics, donor demographics, or treatment conditions between patients that did and did not develop LE. Overall, patients with LE had worse clinical outcomes and overall survival than those without. In addition, they tended to have higher markers of systemic inflammation in the early post-transplant period, including fever, C-reactive protein (CRP), and cytokines. Remarkably, baseline interleukin-6 levels before HSCT were found to be higher in patients who developed LE than those who did not. In addition, analysis of T cell subsets showed impaired expansion of CD25+FOXP3+ regulatory T (Treg) cells in LE compared to non-LE patients despite appropriate reconstitution of the total CD4+ T cell population. Patients that developed LE within the first 30 days of HSCT were likely to have high serum IL-6 among other inflammatory cytokines coupled with suppression of regulatory T cell differentiation. Further work is needed on the mechanisms underlying impaired Treg expansion following HSCT and potential therapies.

SIRT3 Activator Honokiol Inhibits Th17 Cell Differentiation and Alleviates Colitis.

Honokiol (HKL), a natural extract of the bark of the magnolia tree and an activator of the mitochondrial protein sirtuin-3 (SIRT3), has been proposed to possess anti-inflammatory effects. This study investigated the inhibitory effects of HKL on T helper (Th) 17 cell differentiation in colitis. Serum and biopsies from 20 participants with ulcerative colitis (UC) and 18 healthy volunteers were collected for the test of serum cytokines, flow cytometry analysis (FACS), and relative messenger RNA (mRNA) levels of T cell subsets, as well as the expression of SIRT3 and phosphorylated signal transducer and activator of transcription/retinoic acid-related orphan nuclear receptor γt (p-STAT3/RORγt) signal pathway in colon tissues. In vitro, naïve clusters of differentiation (CD) 4 + T cells isolated from the mouse spleen differentiated to subsets including Th1, Th2, Th17, and regulatory T (Treg) cells. Peripheral blood monocytes (PBMCs) from healthy volunteers were induced to the polarization of Th17 cells. After HKL treatment, changes in T cell subsets, related cytokines, and transcription factors were measured. The dextran sulfate sodium (DSS)-induced colitis and interleukin (IL)-10-deficient mice were intraperitoneally injected with HKL. These experiments were conducted to study the effect of HKL on the development, cytokines, and expression of signaling pathway proteins in colitis. Patients with UC had higher serum IL-17 and a higher proportion of Th17 differentiation in blood compared with healthy participants; while IL-10 level and the proportion of Treg cells were lower. Higher relative mRNA levels of RORγt and a lower SIRT3 expression in colon tissues were observed. In vitro, HKL had little effect on the differentiation of naïve CD4+ T cells to Th1, Th2, or Treg cells, but it downregulated IL-17 levels and the Th17 cell ratio in CD4+ T cells from the mouse spleen and human PBMCs under Th17 polarization. Even with a STAT3 activator, HKL still significantly inhibited IL-17 levels. In DSS-induced colitis mice and IL-10 deficient mice treated with HKL, the length of the colon, weight loss, disease activity index, and histopathological scores were improved, IL-17 and IL-21 levels, and the proportion of Th17 cells were decreased. Sirtuin-3 expression was increased, whereas STAT3 phosphorylation and RORγt expression were inhibited in the colon tissue of mice after HKL treatment. Our study demonstrated that HKL could partially protect against colitis by regulating Th17 differentiation through activating SIRT3, leading to inhibition of the STAT3/RORγt signaling pathway. These results provide new insights into the protective effects of HKL against colitis and may facilitate the research of new drugs for inflammatory bowel disease.

High levels of interleukin-6 and triglycerides and low levels of soluble leptin receptors as risk factors for leptin resistance in obese adolescents

Introduction: Obesity is a nutritional disorder that can affect all ages, including teenagers. Obesity can affect gut microbiota and cause increased intestinal permeability. This process leads to interleukin-6 and TNF-α production which can increase leptin levels. The soluble leptin receptor (sLR) is a leptin receptor in the plasma that transports leptin to the hypothalamus. Low sLR numbers are associated with high leptin levels in obesity. Obesity in hyperleptinemia conditions indicates leptin resistance (defects in leptin receptors) which causes hyperphagia and reduces energy expenditure. This study was conducted to prove high TG and IL-6 serum levels and low sLR levels in obese adolescents who have a higher risk of developing leptin resistance than normal adolescents. Methods: This research is a case-control study. The subjects underwent an assessment including food recall, anthropometric status, and lipid profile. The food recall assessment was obtained by means of a questionnaire given to parents. Blood sampling and laboratory examination are carried out by the Prodia® Clinical Laboratory. Data analysis was performed by computer, using the Independent t-test, Mann-Whitney test. Chi-Square test, and analysis of the ROC curve. Results: ROC curve analysis obtained the optimal cut points for TG and IL-6 levels, respectively 101.5 mg/dL (sensitivity 82.1%, specificity 89.7%) and 11.95 pg/mL (sensitivity 84.6%, specificity of 80%), with area under the curve (AUC) values of 0.96 and 0.89, respectively. ROC curve analysis obtained the optimal cut point for sLR levels of 19.3 ng/mL (sensitivity 64.1%, specificity 71.8%) with an AUC value of 0.77. Multivariate analysis using logistic regression found a significant relationship between TG and IL-6 levels on the incidence of hyperleptinemia. Conclusion: This study reinforces the theory of chronic low-grade inflammation and proved that inflammation and high TG levels play a role in hyperleptinemia in obese adolescents.

Abstract 5016: IL-6 influences PIM1 expression in renal cell carcinoma

Abstract Renal cell carcinoma (RCC) is the most common kidney neoplasm, accounting for over 430,000 new cases worldwide and 179,000 deaths annually. The overexpression of the proviral integration site for moloney murine leukemia virus 1 (PIM1) kinase is associated with poor clinical outcomes in patients with RCC. PIM1 is a constitutively active effector serine/threonine kinase with roles in tumor progression including cell proliferation, apoptosis, invasion, and migration. Yet, the mechanisms underlying PIM1 expression and its function in RCC are not fully delineated. IL-6 is a pleiotropic cytokine involved in the activation of the JAK/STAT signaling cascade. High serum IL-6 levels are implicated in the poor prognosis of RCC patients and are hypothesized to contribute to RCC invasion and metastasis. PIM1 is shown to be transcriptionally regulated downstream of JAK/STAT signaling and an IL-6/STAT3/PIM1 axis exists in pancreatic cancer. We thus hypothesize that this pathway also regulates expression of PIM1 in RCC. Here, we explore the levels of PIM1 in RCC and identify potential signaling pathways influencing PIM1 expression. Our results show five RCC cell lines, 769-P, 786-O, ACHN, CAKI-1, and RCC-4 cells overexpress PIM1 relative to normal renal proximal tubule epithelial cells. In RCC cell lines, IL-6 secretion correlates with PIM1 protein levels. Treatment with ruxolitinib, a JAK1/2 inhibitor, leads to a dose and concentration dependent decrease in PIM1 levels. We then tested whether incubation with an IL-6 neutralizing antibody is sufficient to regulate PIM1 protein levels. Indeed, use of an IL-6 antibody resulted in decreased pJAK2 protein and PIM1 protein. Our initial studies suggest that differential expression of PIM1 among RCC cell lines may be linked to autocrine IL-6 signaling. Interestingly, 769-P cells demonstrate increased PIM1 levels but do not secrete IL-6 and neither ruxolitinib treatment nor incubation with an IL-6 neutralizing antibody appear to affect PIM1 levels. Therefore, an IL-6/JAK-independent pathway resulting in increased PIM1 protein levels likely exists in 769-P cells. Further investigation is required to elucidate the contexts of PIM1 regulatory pathways in order to develop novel targeted anti-cancer strategies in RCC. Citation Format: Kimberly S. Meza, Sheldon L. Holder. IL-6 influences PIM1 expression in renal cell carcinoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5016.

Association of preoperative IL-6 levels with overt HE in patients with cirrhosis after TIPS.

HE is a common and dangerous complication after TIPS. The relationship between IL-6 levels and overt HE (OHE) after TIPS is rarely reported.We aimed to explore the relationship between the preoperative serum IL-6 levels and OHE risk after TIPS, and to evaluate its value in predicting the OHE risk. This prospective cohort study included 125 participants with cirrhosis who received TIPS. Logistics regression analyses were performed to explore the relationship between IL-6 and OHE risk, and the receiver operating characteristic analysis was used to compare the predictive power of IL-6 and other indexes. Among 125 participants, 44 (35.2%) participants developed OHE after TIPS. Logistics regression showed preoperative IL-6 was associated with a higher OHE risk after TIPS in different models (all p < 0.05). Participants with IL-6 > 10.5pg/mL had a higher cumulative incidence of OHE after TIPS than those with IL-6 ≤ 10.5pg/mL (log-rank = 0.0124). The predictive power of IL-6 (AUC = 0.83) for the OHE risk after TIPS was higher than that of other indexes. Age (RR = 1.069, p = 0.002) and IL-6 (RR = 1.154, p < 0.001) were independent risk factors for OHE after TIPS. IL-6 was also a risk factor for the occurrence of coma in patients with OHE (RR = 1.051, p = 0.019). Preoperative serum IL-6 levels are closely related to the occurrence of OHE in patients with cirrhosis after TIPS. Patients with cirrhosis with high serum IL-6 levels following TIPS were at a higher risk of developing severe HE.

Mechanisms of systemic low-grade inflammation in HIV patients on long-term suppressive antiretroviral therapy: the inflammasome hypothesis.

We aimed to determine the contribution of inflammasome activation in chronic low-grade systemic inflammation observed in patients with HIV (PWH) on long-term suppressive antiretroviral therapy (ART) and to explore mechanisms of such activation. Forty-two PWH on long-term suppressive ART (HIV-RNA < 40 copies/ml) were compared with 10 HIV-negative healthy controls (HC). Inflammasome activation was measured by dosing mature interleukin (IL)-1β and IL-18 cytokines in patient serum. We explored inflammasome pathways through ex vivo stimulation of PWH primary monocytes with inflammasome activators; expression of inflammasome components by transcriptomic analysis; and metabolomics analysis of patient sera. Median (Q1; Q3) age, ART and viral suppression duration in PWH were 54 (48; 60), 15 (9; 20) and 7.5 (5; 12) years, respectively. Higher serum IL-18 was measured in PWH than in HC (61 (42; 77) vs. 36 (27-48 pg/ml), P = 0.009); IL-1β was detected in 10/42 PWH (0.5 (0.34; 0.80) pg/ml) but not in HC. Monocytes from PWH did not produce more inflammatory cytokines in vitro, but secretion of IL-1β in response to NLRP3 inflammasome stimulation was higher than in HC. This was not explained at the transcriptional level. We found an oxidative stress molecular profile in PWH sera. HIV infection with long-term effective ART is associated with a serum inflammatory signature, including markers of inflammasome activation, and an increased activation of monocytes upon inflammasome stimulation. Other cells should be investigated as sources of inflammatory cytokines in PWH. Oxidative stress might contribute to this chronic low-grade inflammation.

High serum IL-6 correlates with reduced clinical benefit of atezolizumab and bevacizumab in unresectable hepatocellular carcinoma

We elucidated the clinical and immunologic implications of serum IL-6 levels in patients with unresectable hepatocellular carcinoma (HCC) treated with atezolizumab and bevacizumab (Ate/Bev). We prospectively enrolled 165 patients with unresectable HCC (discovery cohort: 84 patients from three centres; validation cohort: 81 patients from one centre). Baseline blood samples were analysed using a flow cytometric bead array. The tumour immune microenvironment was analysed using RNA sequencing. In the discovery cohort, clinical benefit 6 months (CB6m) was defined as complete or partial response, or stable disease for ≥6 months. Among various blood-based biomarkers, serum IL-6 levels were significantly higher in participants without CB6m than in those with CB6m (mean 11.56 vs. 5.05pg/ml, p= 0.02). Using maximally selected rank statistics, the optimal cut-off value for high IL-6 was determined as 18.49pg/ml, and 15.2% of participants were found to have high IL-6 levels at baseline. In both the discovery and validation cohorts, participants with high baseline IL-6 levels had a reduced response rate and worse progression-free and overall survival after Ate/Bev treatment compared with those with low baseline IL-6 levels. In multivariable Cox regression analysis, the clinical implications of high IL-6 levels persisted, even after adjusting for various confounding factors. Participants with high IL-6 levels showed reduced interferon-γ and tumour necrosis factor-α secretion from CD8+ T cells. Moreover, excess IL-6 suppressed cytokine production and proliferation of CD8+ T cells. Finally, participants with high IL-6 levels exhibited a non-T-cell-inflamed immunosuppressive tumour microenvironment. High baseline IL-6 levels can be associated with poor clinical outcomes and impaired T-cell function in patients with unresectable HCC after Ate/Bev treatment. Although patients with hepatocellular carcinoma who respond to treatment with atezolizumab and bevacizumab exhibit favourable clinical outcomes, a fraction of these still experience primary resistance. We found that high baseline serum levels of IL-6 correlate with poor clinical outcomes and impaired T-cell response in patients with hepatocellular carcinoma treated with atezolizumab and bevacizumab.

Utility of renal biopsy in differentiating idiopathic multicentric Castleman disease from IgG4-related disease.

Idiopathic multicentric Castleman disease (iMCD) is a subtype of human herpesvirus type 8 (HHV-8)-related Castleman disease that causes multi-organ damage, including kidney damage due to polyclonal lymphoproliferation and interleukin (IL)-6-induced cytokine storm. However, its renal pathological findings are unclear. We report the case of a woman in her 80s who was diagnosed with iMCD based on renal pathological findings. Five years ago, hypergammaglobulinemia was detected, and her renal function declined. Renal biopsy revealed plasma cells infiltrating the stroma. Immunostaining revealed numerous IgG4-positive plasma cells. The serum IgG4 level was high, and she was initially diagnosed with IgG4-related disease (IgG4-RD) and treated with steroids. However, the therapeutic effect was poor. On re-examination, computed tomography revealed lymphadenopathy around the aorta and spleen. Renal histopathology showed numerous IL-6-positive plasma cells. Anemia and C-reactive protein (CRP) positivity persisted despite steroid administration. HHV-8 was negative, and polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes syndrome was not suspected. Thus, iMCD was diagnosed. Based on previous reports, there is no significant difference in IgG4 levels between iMCD and IgG4-RD, and IgG4-positive plasma cell infiltrates were observed in iMCD-affected organs. Therefore, it may be difficult to distinguish iMCD from IgG4-RD. In this case, high-serum IL-6 and CRP were observed, which are usually not seen in IgG4-RD but are common findings in iMCD, leading to the diagnosis. Patients with deep lymphadenopathy may be diagnosed with iMCD based on renal pathological findings. Renal biopsy is recommended for patients with suspected iMCD and decreased renal function.

LOW CD8+ COUNT CORRELATION WITH INFLAMMATORY MARKERS IN ACUTE COVID-19

LOW CD8+ COUNT CORRELATION WITH INFLAMMATORY MARKERS IN ACUTE COVID-19