Associations of non-invasive indices of liver steatosis and fibrosis with progressive kidney impairment in adults with type 2 diabetes.

AIMS: Longitudinal data linking non-alcoholic fatty liver disease to kidney dysfunction in type 2 diabetes (T2D) are limited. This study evaluated the associations of non-invasive indices of liver steatosis and liver fibrosis with kidney impairment, and the mediatory role of the pro-angiogenic factor leucine-rich α-2 glycoprotein 1 (LRG1). METHODS: T2D adults (n = 2057) were followed for a mean period of 6.1 ± 1.6 years. Baseline liver steatosis [(hepatic steatosis index (HSI) and Zhejiang University index (ZJU)] and liver fibrosis [aspartate transaminase/alanine transaminase ratio (AAR) and BARD] indices derived from composite scoring systems were calculated. Plasma LRG1 levels were quantified using immunoassay. The study outcomes were progressive kidney function decline defined as estimated glomerular filtration rate (eGFR) decline of ≥ 40% and albuminuria progression defined as an increase in albuminuria category. RESULTS: Cross-sectionally, liver steatosis and liver fibrosis indices were associated with increased albuminuria (urinary albumin/creatinine ratio ≥ 30 µg/mg) and reduced renal function (eGFR < 60 mL/min/1.73 m2) after covariate adjustment, respectively. Approximately 32% of the participants experienced progressive kidney function decline, while 38% had albuminuria worsening over time. Longitudinal analysis revealed that baseline AAR (hazard ratio: 1.56; 95% CI 1.15-2.11) and BARD (hazard ratio: 1.16, 95% CI 1.04-1.28) predicted progressive kidney function decline, partly mediated by LRG1. In contrast, liver steatosis (HSI and ZJU) but not liver fibrosis (AAR and BARD) indices were independently associated with albuminuria progression. CONCLUSIONS: Increased liver steatosis scores were associated with albuminuria deterioration. Conversely, liver fibrosis indices may be associated with progressive kidney function decline, potentially driven by increased inflammation and angiogenesis.

Association between neutrophil/lymphocyte ratio and kidney impairment in type 2 diabetes mellitus: A role of extracellular water/total body water ratio.

AIMS: We explored the predictive utility of baseline neutrophil/lymphocyte ratio (NLR), which reflects a systemic inflammatory tone, in kidney impairment in type 2 diabetes mellitus (T2DM); and investigated the effect of extracellular water/total body water (ECW/TBW) ratio on the relationship. METHODS: This longitudinal study included 1,224 T2DM adults recruited from a single centre. Cox regression analyses examined the association between NLR and progressive kidney function decline or albuminuria progression. Improvements in risk discrimination were assessed using Harrell's concordance-statistics. The mediatory role of ECW/TBW ratio estimated by bioelectrical impedance was evaluated. RESULTS: Higher baseline NLR levels were observed in cases with kidney function decline or albuminuria progression over a median 2-year follow-up. NLR independently predicted progressive kidney function decline (hazard ratio:1.39, 95% CI:1.21-1.60, P < 0.001) or albuminuria progression (hazard ratio:1.34, 95% CI:1.08-1.68, P = 0.009). Addition of NLR to a base model comprising demographics, T2DM duration, metabolic and renal parameters, and medications significantly improved the risk discrimination of kidney function decline (P = 0.022) but not albuminuria progression. ECW/TBW ratio accounted for 19.7% of the total effect between NLR and kidney function loss. CONCLUSIONS: Increased NLR reflecting systemic inflammation is associated with progressive kidney function decline in T2DM, partially explained by dysregulated body fluid balance.

Association of Baseline Triglyceride-Glucose Index with Poor Glycemic Control and Diabetes Remission After Metabolic Surgery.

PURPOSE: The utility of insulin resistance (IR) as a predictor of diabetes remission after metabolic surgery is not well-defined. We assessed the association of baseline surrogate IR indices including triglyceride-glucose (TyG) index and homeostatic model assessment for IR (HOMA-IR) with glycemic control and diabetes remission after metabolic surgery. MATERIALS AND METHODS: Patients with type 2 diabetes scheduled for metabolic surgery were recruited at a single-center (n = 149; age: 44 ± 10 years, 47.7% men, body mass index: 41.5 ± 7.5 kg/m2), and followed-up for 12 months postoperatively. The relationships between the IR indices and poor glycemic control (HbA1c ≥ 7%) at baseline or complete diabetes remission (HbA1c < 6% without glucose-lowering medications at 12 months) post-surgery were examined. RESULTS: Elevated TyG index was associated with poor glycemic control cross-sectionally. Compared with non-remitters, lower baseline TyG index levels were observed in individuals with complete diabetes remission after surgery (P = 0.012); whereas HOMA-IR was not significantly different. Consistently, the proportion of diabetes non-remitters (compared to remitters) increased with increasing TyG tertiles from 1 to 3 (P = 0.015). Both TyG index (relative risk = 0.62, 95% CI = 0.42-0.91, P = 0.014) and TyG tertile 1 (relative risk = 1.99, 95% CI = 1.25-3.24, P = 0.003) independently predicted diabetes remission. The TyG index identified diabetes remission with an area under the curve of 0.68. The optimal TyG threshold was 9.41, yielding a sensitivity of 69.6%, specificity of 60.9%, positive predictive value of 64.0%, and negative predictive value of 66.7%. CONCLUSION: TyG index, previously suggested to predominantly reflect muscle IR, outperforms HOMA-IR as an IR indicator associated with glycemic control and diabetes remission after metabolic surgery.

Association between depressive symptoms and pulse wave velocity is mediated by increased adiposity in older adults with type 2 diabetes.

Background: Studies investigating the association between depression and aortic stiffness in older patients with type 2 diabetes are lacking. We postulated an association between depressive symptoms and aortic stiffness, and this relationship may be mediated by increased adiposity. Methods: We analyzed participants with type 2 diabetes aged 55 years or older (n = 958). We measured aortic stiffness using carotid-femoral pulse wave velocity (cut-off ≥ 12 m/s) using the tonometry method. We defined depressive symptoms as a score of greater than 5 on the Geriatric Depression Scale-15 (GDS-15). Adiposity indices we assessed were body mass index, waist circumference, waistto-height ratio, visceral fat area and fat mass. Results: Among the participants, 27.2% had aortic stiffness, of whom 6.5% had depressive symptoms. Score on the GDS-15 was correlated with pulse wave velocity, and both variables were correlated with the adiposity markers we analyzed (all p < 0.05). Depressive symptoms were associated with pulse wave velocity (B = 1.79, 95% confidence interval [CI] 0.83-2.75) or aortic stiffness (risk ratio 1.60, 95% CI 1.10-2.33) in the unadjusted model. The association persisted after controlling for demographics, duration of diabetes, glycated hemoglobin, comorbidities and medications. Further adjustment for visceral fat area and fat mass in separate models reduced the association between depressive symptoms and pulse wave velocity or aortic stiffness. Mediation models revealed that the mediation proportions of fat mass and visceral fat area on the association between depressive symptoms and pulse wave velocity were 11.8% and 9.7%, respectively. A preliminary analysis of longitudinal data (n = 184) showed similar findings. Limitations: Causality cannot be inferred from the associations we observed. Conclusion: Depressive symptoms are associated with elevated pulse wave velocity in older people with type 2 diabetes, and this relationship may be partially mediated by increased adiposity.

Long-Term Observation of a Man With Severe Obesity and Undiagnosed Monogenic Diabetes Serendipitously Treated With Metabolic Surgery.

A 43-year-old man, with severe obesity (43 kg/m2) and diabetes (presumed as type 2 diabetes [T2D]), underwent vertical sleeve gastrectomy in 2009 and Roux-en-Y gastric bypass in 2013. Recently, whole exome sequencing (conducted to search for monogenic obesity) serendipitously revealed that the individual harbored a heterozygous glucokinase (GCK) variant p.(Arg422Leu) that was bioinformatically strongly predicted to be likely pathogenic. Therefore, he is likely to have concomitant maturity-onset diabetes of the young (MODY) type 2 (GCK-MODY). A retrospective evaluation of the clinical data showed that the subject was diagnosed with T2D (given his severe obesity) in 2005 and was treated with oral antidiabetic monotherapy. His hyperglycemia was mostly mild (HbA1c [hemoglobin] < 8.1%), consistent with that of MODY2, despite severe obesity. After vertical sleeve gastrectomy, complete diabetes remission (HbA1c <6.0% and fasting plasma glucose <5.6 mmol/L without use of antidiabetic medication) was achieved. The percentage of maximum body weight loss attained after surgery was 23.6%. Euglycemia was maintained during the subsequent decade, up to the last follow-up in 2019, without any sign of hypoglycemia. In conclusion, we report a decade-long clinical experience of a man with severe obesity and diabetes likely due to the coexistence of GCK-MODY and T2D, serendipitously treated with metabolic surgery. Interestingly, metabolic surgery was effective and safe for him.

Metabolic Surgery Diabetes Remission (MDR) Score: a New Preoperative Scoring System for Predicting Type 2 Diabetes Remission at 1 Year After Metabolic Surgery in the Singapore Multi-ethnic Asian Setting.

PURPOSE: The utility of available scoring systems for type 2 diabetes (T2D) remission prediction after metabolic surgery has not been defined in a multi-ethnic Asian population like Singapore. We sought to assess the predictive performance of the Asia-developed ABCD scoring system for T2D remission after metabolic surgery, and develop a new algorithm to improve prediction. MATERIALS AND METHODS: We conducted a retrospective analysis of adults with T2D who underwent either Roux-en-Y gastric bypass or sleeve gastrectomy between 2007 and 2018, and followed for 1 year postoperatively (n = 114, mean age 46 ± 9 years, 48.2% men, body mass index 40.1 ± 6.6 kg/m2). The primary outcome was complete T2D remission defined as HbA1c < 6% without the use of anti-diabetic medication at 1 year after surgery. RESULTS: Complete T2D remission was observed in 47.4% of subjects at 1 year post-surgery. Stepwise logistic regression identified preoperative age, T2D duration, HbA1c, and ß-cell function (estimated by the homeostasis model) as predictors of complete T2D remission. Based on these four variables, we constructed a new 10-point scoring system named Metabolic surgery Diabetes Remission (MDR) score. Compared with ABCD, MDR produced fewer misclassifications at the mid-high scores, achieving a predictive accuracy of 71-100% at 6 points and above. In addition, MDR achieved a higher area under the receiver operating characteristic curve than ABCD for the primary outcome (0.79 versus 0.67, P = 0.007). CONCLUSION: MDR may serve as a useful clinical scoring system for predicting short-term T2D remission after metabolic surgery in Singapore's multi-ethnic Asian cohort.

Association of traditional and novel measures of central obesity with cognitive performance in older multi-ethnic Asians with type 2 diabetes.

Literature evaluating the relationship between central obesity and cognitive deficits in type 2 diabetes (T2DM) remains scarce. This cross-sectional analysis explored the association of novel and traditional central obesity measures with cognitive performance in older (aged ≥60 years) non-demented multi-ethnic Asians with T2DM, including a stratified analysis by body mass index (BMI). Cognitive function was assessed using the Repeatable Battery for the Assessment of Neuropsychological Status. Central obesity measures including visceral fat area (VFA), waist circumference, waist:hip ratio, waist:height ratio, abdominal volume index, body roundness index and conicity index were measured and/or computed. In our cohort (N = 677; mean age = 67 ± 5 years, 51.7% men), VFA emerged as an associate of overall cognitive performance after covariate adjustment and Bonferroni correction (ß = -.10, 95% CI = -0.18, -0.03), outperforming the other adiposity indices. Specifically, VFA was inversely associated with delayed memory and language scores. Additionally, compared with normal-weight individuals, excess visceral obesity (VFA ≥100 cm2 ) was independently associated with lower cognitive scores to a greater extent in normal BMI (<23 kg/m2 ) adults than in those with high BMI (≥23 kg/m2 ). Assessment and management of visceral adiposity may help to prevent cognitive decline in older people with T2DM, and reduce the global burden of dementia in ageing populations.

Role of endothelium-independent vasodilation in the relationship between visceral adiposity and reduced cognitive performance in older adults with type 2 diabetes.

OBJECTIVE: In this cross-sectional analysis, we sought to assess the relationship of adiposity and forearm microvascular reactivity with cognitive dysfunction among older Asians with type 2 diabetes (T2D). METHODS: Subjects with T2D aged ≥ 55 years were analyzed (N = 907). Cognitive performance was assessed using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and Mini-Mental State Exam (MMSE). Visceral fat area (VFA) was estimated by tetrapolar multi-frequency bioimpedance. Forearm microvascular endothelium-dependent vasodilation (EDV) and endothelium-independent vasodilation (EIV) were assessed by laser Doppler imaging with iontophoresis. RESULTS: RBANS total score was correlated with VFA, EDV, and EIV (all P < .05). However, VFA was correlated with EIV, but not with EDV. Multivariable linear regression showed significant association between VFA and RBANS total score (B = -0.02, 95% CI= -0.03 to -0.01) or memory (immediate and delayed) index scores. These associations were attenuated after adjustment for EIV. Mediation analysis showed that EIV partially mediated the relationship between visceral adiposity and RBANS scores (all Sobel tests P < .05). EIV also mediated the relationship between VFA and MMSE score. CONCLUSIONS: Impaired endothelium-independent vascular smooth muscle reactivity may exert a mediatory effect on the association between increased visceral adiposity and decreased cognitive performance in older adults with T2D.

Ethnic disparities in relationships of obesity indices with telomere length in Asians with type 2 diabetes.

BACKGROUND: Obesity and shorter telomeres increase the risk for diabetes complications and mortality. However, the relationship between obesity and telomere length in diverse Asian populations with type 2 diabetes (T2D) is not well understood. This study examined the association of baseline and changes in obesity indices with telomere length in multiethnic Asian populations with T2D. METHODS: Leukocyte telomere length (LTL) was measured by quantitative polymerase chain reaction in the SMART2D cohort (n = 1431 at baseline, n = 1039 after 3.2 years median follow-up). Associations between obesity indices and LTL were assessed by linear regression. RESULTS: Compared with Chinese, LTL was longer in Malays (P < 0.0001) and similar in Indians. Cross-sectionally, body mass index (BMI)-adjusted (residual) visceral fat area (VFA; ß = -0.004, P = 0.006), and waist-to-hip ratio (ß = -1.95, P = 0.030) were significantly associated with LTL in Chinese but not in Malays and Indians. Changes in BMI (r = -0.080; P = 0.053) and VFA (r = -0.126; P = 0.002) were inversely correlated with changes in LTL only in Chinese. Furthermore, in Chinese, 1-SD incremental changes in BMI (ß = -0.070; P = 0.040) and VFA (ß = -0.088, P = 0.028) were significantly associated with larger telomere attrition, independent of age, sex, diabetes condition, baseline LTL, obesity, and inflammation markers. CONCLUSIONS: Three-year changes in BMI and VFA were associated with telomere dynamics in Chinese but not in Malays and Indians with T2D. Reducing obesity may reduce the risk of diabetes complications associated with shorter LTL in the Chinese population.

Gain in adiposity over 3 years is associated with progressive renal decline in multi-ethnic South-east Asians with type 2 diabetes.

BACKGROUND: This study evaluated the association between gain in adiposity and renal decline in a large prospective multiethnic South-east Asian cohort with type 2 diabetes mellitus (T2DM). METHODS: Three years after the baseline visit, 2057 T2DM subjects were recalled for reassessment. The final cohort comprised 1014 subjects and was categorized into tertiles based on changes in body weight (ΔWt), body mass index (ΔBMI), visceral fat area (ΔVFA), and BMI-adjusted VFA (ΔVFABMI ). Outcomes included annual and rapid (≥3 mL/min per 1.73 m2 per year) decline in estimated glomerular filtration rate (eGFR) and progression of albuminuria. RESULTS: Participants (mean [±SD] age 57 ± 11 years, 48.8% women, BMI 27.7 ± 5.4 kg/m2 ) exhibited a median annual decline in eGFR of 1.0 mL/min per 1.73 m2 . Compared with the lower tertiles, Tertile 3 of ΔWt, ΔBMI, ΔVFA, and ΔVFABMI had the highest anthropometric increase, albeit of modest magnitude, and this was accompanied by the worst renal outcomes (all P < 0.05). The relationship between annual eGFR decline and Tertile 3 of ΔWt, ΔBMI, and ΔVFABMI persisted after multivariate adjustment in men but not in women. In addition, Tertile 3 of ΔWt, ΔBMI, ΔVFA, and ΔVFABMI predicted rapid eGFR decline. Anthropometric gains were also associated with progression of albuminuria. CONCLUSIONS: Modest longitudinal gain in adiposity was associated with progressive renal decline in T2DM patients, suggesting that increased adiposity over time adversely affects renal outcomes. Therefore, a carefully designed weight-neutral or -loss antidiabetic treatment regimen is important when managing T2DM in the clinic.

Association of the anti-angiogenic factor secreted protein and rich in cysteine (SPARC) with vascular complications among Chinese type 2 diabetic patients in Singapore.

AIMS: This study evaluated the association of the anti-angiogenic SPARC with known angiogenesis-associated factors and diabetes-related micro- and macro-vascular complications in a Singapore Chinese cohort with type 2 diabetes (T2DM). METHODS: Plasma SPARC was measured by immunoassay in 438 T2DM adults (mean age:58±11years). RESULTS: Higher SPARC levels in subjects stratified by SPARC tertiles displayed decreased pro-angiogenic adiponectin, osteopontin, vascular cell adhesion molecule (VCAM)-1 and matrix metalloproteinase (MMP)-2 concentrations (all p<0.05). The anti-angiogenic pigment epithelium-derived factor (PEDF) level was not statistically different among the SPARC tertiles. Age-adjusted partial correlation revealed significant associations of SPARC with adiponectin, osteopontin, VCAM-1, MMP-2, and PEDF (all p<0.05). Lower SPARC was accompanied by less favorable estimated glomerular filtration rate (eGFR) and carotid-femoral pulse wave velocity (PWV) readings (all p<0.05). Conversely, ankle-brachial index (ABI) reduced with increasing SPARC (p=0.048). The eGFR (B=0.834, p=0.019), PWV (B=-7.925, p=0.009), and ABI (B=-142.160, p=0.010) remained as determinants of SPARC after confounder adjustment. Moreover, individuals in the lowest SPARC tertile had increased odds of aortic stiffness (OR=1.900, 95% CI=1.103-3.274) but reduced odds of peripheral arterial disease (OR=0.400, 95% CI=0.175-0.919). However, SPARC was not independently associated with chronic kidney disease. CONCLUSIONS: The anti-angiogenic SPARC may be associated with the pathophysiology of diabetes-related macrovascular complications.

Baseline predictors of aortic stiffness progression among multi-ethnic Asians with type 2 diabetes.

BACKGROUND AND AIMS: This 3-year prospective study aimed to identify baseline parameters that predicted the progression of carotid-femoral pulse wave velocity (cf-PWV), which was used to evaluate aortic stiffness, among Singapore's multi-ethnic Asians with type 2 diabetes (T2DM). METHODS: The cf-PWV was measured by the gold-standard tonometry method in 994 T2DM subjects at baseline and follow-up. The annual rate of cf-PWV change was calculated, and individuals above the 90th percentile with rate≥1.42 m/s per year were regarded as rapid progressors (n = 104). In a subgroup analysis of subjects with normal cf-PWV at 1st visit (n = 611), incident aortic stiffness was defined as follow-up cf-PWV≥10 m/s (n = 188). RESULTS: The total cohort (mean age:57 ± 10 years; 53.4% Chinese, 20.4% Malay, 22.9% Indian, 3.2% 'Others') displayed a median annual cf-PWV progression rate of 0.2 m/s. Adjusted multivariate regression analyses showed that baseline age, cf-PWV and body mass index (BMI) constantly predicted follow-up cf-PWV, annual cf-PWV progression rate, rapid cf-PWV progression, and incident aortic stiffness. Paradoxically, lower baseline cf-PWV was associated with elevated annual cf-PWV progression rate and rapid progressors. This inverse relationship remained significant across ethnicities after ethnic stratification. Higher BMI independently predicted cf-PWV progression in Chinese and Indians, but not in Malay and 'Others' ethnic groups. Increased age was a significant predictor in Chinese and 'Others' ethnicities. CONCLUSIONS: We demonstrated that baseline BMI is a modifiable independent risk factor of cf-PWV progression and incident aortic stiffness. Therefore, better obesity management may impede aortic stiffness in Singapore's T2DM patients, especially in the Chinese and Indians.

HepaCAM associates with connexin 43 and enhances its localization in cellular junctions.

HepaCAM (GlialCAM) is frequently deleted in carcinomas, and reintroduction of hepaCAM into transformed cell lines reduces cellular growth and induces senescence. Mutations in HEPACAM give rise to the neurodegenerative disease megalencephalic leukoencephalopathy with subcortical cysts (MLC) since mutated hepaCAM prevents shuttling of MLC1 protein to astrocytic junctions in the plasma membrane. Here we identify that hepaCAM associates with connexin 43, a main component of gap junctions, and enhances connexin 43 localization to the plasma membrane at cellular junctions. HepaCAM also increases the levels of connexin 43, not by enhancing its transcription but by stabilizing connexin 43 protein. In the absence of hepaCAM, connexin 43 undergoes a faster degradation via the lysosomal pathway while proteasomal degradation seems not to be involved. Mutations in hepaCAM that cause MLC, or neutralization of hepaCAM by antibodies disrupt its association with connexin 43 at cellular junctions. By discovering the requirement of hepaCAM for localizing connexin 43, a well-established tumor suppressor, to cellular junctions and stabilizing it there, this study suggests a mechanism by which deletion of hepaCAM may support tumor progression.

Evaluation of body adiposity index as a predictor of aortic stiffness in multi-ethnic Asian population with type 2 diabetes.

Cardiovascular disease is the leading cause of morbidity and mortality in type 2 diabetes mellitus. We evaluated the predictive ability of the recently developed body adiposity index for aortic stiffness, an intermediate endpoint of cardiovascular disease, in a cross-sectional multi-ethnic Asian type 2 diabetes mellitus cohort (N = 1408). AS was estimated using carotid-femoral pulse wave velocity measured by applanation tonometry. Body adiposity index was computed as hip circumference/(height)(1.5) - 18. Compared to body mass index, waist circumference and visceral fat area, body adiposity index displayed the weakest association with pulse wave velocity (r = 0.077, 0.096, 0.134 and 0.058, respectively; all p < 0.05). Interestingly, the relationship between measurements of obesity and pulse wave velocity was ethnic dependent - body mass index, body adiposity index, waist circumference and visceral fat area consistently predicted pulse wave velocity only in Indians but not others. In multi-variable analysis, body mass index was a significant determinant of pulse wave velocity in all ethnicities. In conclusion, body adiposity index is a weak predictor of aortic stiffness (when compared with body mass index) in Asians with type 2 diabetes mellitus.

Regulation of myelopoiesis by CD137L signaling.

CD137 ligand (CD137L) has emerged as a powerful regulator of myelopoiesis that links emergency situations, such as infections, to the generation of additional myeloid cells, and to their activation and maturation. CD137L is expressed on the cell surface of hematopoietic stem and progenitor cells (HSPC) and antigen presenting cells (APC) as a transmembrane protein. The signaling of CD137L into HSPC induces their proliferation and differentiation to monocytes and macrophages, and in monocytes CD137L signaling induces differentiation to potent dendritic cells (DC). CD137L signaling is initiated by CD137 which is expressed by T cells, once they become activated. Some of these activated, CD137-expressing T cells migrate from the site of infection to the bone marrow where they interact with HSPC to induce myelopoiesis, or they induce monocyte to DC differentiation locally at the site of infection. Therapeutically, induction of CD137L signaling can be utilized to reinitiate myeloid differentiation in acute myeloid leukemia cells, and to generate potent DC for immunotherapy.

Tumor necrosis factor receptor 1 associates with CD137 ligand and mediates its reverse signaling.

Reverse signaling through CD137 ligand (CD137L) potently activates monocytes. However, the underlying mechanism is not well elucidated. This study provides evidence that tumor necrosis factor receptor 1 (TNFR1) acts as a coreceptor for CD137L and mediates CD137L signaling. CD137L colocalizes with TNFR1 on the plasma membrane and binds directly to TNFR1 via its extracellular domain. Using the human monocytic THP-1 cell line, we demonstrate that engagement of CD137L by recombinant CD137 protein promotes cell adhesion, apoptosis, expression of CD14, and production of IL-8 and tumor necrosis factor (TNF). Concomitantly, the expression of TNFR1 protein is down-regulated in response to CD137L activation, due to enhanced extracellular release and internalization of TNFR1. Activation of TNFR1 by TNF protein additively augments CD137L-induced IL-8 expression. Conversely, inhibition of TNFR1 activity by a TNFR1-neutralizing antibody inhibits CD137L-mediated cell adhesion, cell death, CD14 expression, and IL-8 production. Taken together, these data show that TNFR1 associates with CD137L and is required for CD137L reverse signaling.

Expression of CD137 on Hodgkin and Reed-Sternberg cells inhibits T-cell activation by eliminating CD137 ligand expression.

Hodgkin lymphoma is caused by a minority population of malignant Hodgkin and Reed-Sternberg (HRS) cells that recruit an abundance of inflammatory cells. The long-term survival of HRS cells among the vast majority of immune cells indicates that they have developed potent immune escape mechanisms. We report that the TNF receptor family member CD137 (TNFRSF9) is expressed on HRS cells, while normal B cells, from which HRS cells are most often derived, do not express CD137. In 48 of 53 cases of classical Hodgkin lymphoma, CD137 was detected on HRS cells. Ectopically expressed CD137 transferred by trogocytosis from HRS cells to neighboring HRS and antigen-presenting cells, which constitutively express the CD137 ligand (CD137L and TNFSF9), became associated with CD137L and the CD137-CD137L complex was internalized. Disappearance of CD137L from the surface of HRS and antigen-presenting cells led to reduced costimulation of T cells through CD137, reducing IFN-γ release and proliferation. Our results reveal a new regulatory mechanism for CD137L expression that mediates immune escape by HRS cells, and they identify CD137 as a candidate target for immunotherapy of Hodgkin lymphoma.

The roles of cell adhesion molecules in tumor suppression and cell migration: a new paradox.

In addition to mediating cell adhesion, many cell adhesion molecules act as tumor suppressors. These proteins are capable of restricting cell growth mainly through contact inhibition. Alterations of these cell adhesion molecules are a common event in cancer. The resulting loss of cell-cell and/or cell-extracellular matrix adhesion promotes cell growth as well as tumor dissemination. Therefore, it is conventionally accepted that cell adhesion molecules that function as tumor suppressors are also involved in limiting tumor cell migration. Paradoxically, in 2005, we identified an immunoglobulin superfamily cell adhesion molecule hepaCAM that is able to suppress cancer cell growth and yet induce migration. Almost concurrently, CEACAM1 was verified to co-function as a tumor suppressor and invasion promoter. To date, the reason and mechanism responsible for this exceptional phenomenon remain unclear. Nevertheless, the emergence of these intriguing cell adhesion molecules with conflicting roles may open a new chapter to the biological significance of cell adhesion molecules.

The immunoglobulin-like cell adhesion molecule hepaCAM induces differentiation of human glioblastoma U373-MG cells.

Subsequent to our identification of a novel immunoglobulin-like cell adhesion molecule hepaCAM, we showed that hepaCAM is frequently lost in diverse human cancers and is capable of modulating cell motility and growth when re-expressed. Very recently, a molecule identical to hepaCAM (designated as GlialCAM) was found highly expressed in glial cells of the brain. Here, we demonstrate that hepaCAM is capable of inducing differentiation of the human glioblastoma U373-MG cells. Expression of hepaCAM resulted in a significant increase in the astrocyte differentiation marker glial fibrillary acid protein (GFAP), indicating that hepaCAM promotes glioblastoma cells to undergo differentiation. To determine the relationship between hepaCAM expression level and cell differentiation, we established two U373-MG cell lines expressing hepaCAM at different levels. The results revealed that high-level hepaCAM triggered a clear increase in GFAP expression as well as morphological changes characteristic of glioblastoma cell differentiation. Furthermore, high expression of hepaCAM significantly accelerated cell adhesion but inhibited cell proliferation and migration. Concomitantly, deregulation of cell cycle regulatory proteins was detected. Expectedly, the differentiation was noticeably less apparent in cells expressing low-level hepaCAM. Taken together, our findings suggest that hepaCAM induces differentiation of the glioblastoma U373-MG cells. The degree of cell differentiation is dependent on the expression level of hepaCAM.

The immunoglobulin-like cell adhesion molecule hepaCAM modulates cell adhesion and motility through direct interaction with the actin cytoskeleton.

Previously, we reported the identification of a novel immunoglobulin-like cell adhesion molecule hepaCAM that promotes cell-extracellular matrix (ECM) interactions including cell adhesion and motility. Cell-ECM interactions are known to be directed by the actin cytoskeleton. In this study, we examined the association of hepaCAM with the actin cytoskeleton. We found that hepaCAM was partially insoluble in Triton X-100 and colocalized with the actin cytoskeleton on the plasma membrane. Disruption of F-actin decreased the detergent insolubility and disturbed the subcellular localization of hepaCAM. Coimmunoprecipitation and F-actin cosedimentation assays revealed that hepaCAM directly bound to F-actin. In addition, we constructed three N- and C-terminal domain-deleted mutants of hepaCAM to determine the actin-binding region as well as to evaluate the effect of the domains on the biological function of hepaCAM. Detergent solubility assays showed that the cytoplasmic domain of hepaCAM might be required for actin association. However, deletion of either the extracellular or the cytoplasmic domain of hepaCAM abolished actin coprecipitation as well as delayed cell-ECM adhesion and cell motility. The data suggest that an intact hepaCAM protein is critical for establishing a stable physical association with the actin cytoskeleton; and such association is important for modulating hepaCAM-mediated cell adhesion and motility.