Elevated Serum Interleukin-6 Levels Research Articles

Short‐Term Lenalidomide (Revlimid) Administration Ameliorates Cardiomyocyte Contractile Dysfunction in ob/ob Obese Mice

Lenalidomide is a potent immunomodulatory agent capable of downregulating proinflammatory cytokines such as tumor necrosis factor-α (TNF-α) and upregulating anti-inflammatory cytokines. Lenalidomide has been shown to elicit cardiovascular effects, although its impact on cardiac function remains obscure. This study was designed to examine the effect of lenalidomide on cardiac contractile function in ob/ob obese mice. C57BL lean and ob/ob obese mice were given lenalidomide (50 mg/kg/day, p.o.) for 3 days. Body fat composition was assessed by dual-energy X-ray absorptiometry. Cardiomyocyte contractile and intracellular Ca(2+) properties were evaluated. Expression of TNF-α, interleukin-6 (IL-6), Fas, Fas ligand (FasL), the short-chain fatty acid receptor GPR41, the NFκB regulator IκB, endoplasmic reticulum (ER) stress, the apoptotic protein markers Bax, Bcl-2, caspase-8, tBid, cytosolic cytochrome C, and caspase-12; and the stress signaling molecules p38 and extracellular signal-regulated kinase (ERK) were evaluated by western blot. ob/ob mice displayed elevated serum TNF-α and IL-6 levels, fat composition and glucose intolerance, the effects of which except glucose intolerance and fat composition were attenuated by lenalidomide. Cardiomyocytes from ob/ob mice exhibited depressed peak shortening (PS) and maximal velocity of shortening/relengthening, prolonged time-to-PS and time-to-90% relengthening as well as intracellular Ca(2+) mishandling, which were ablated by lenalidomide. Western blot analysis revealed elevated levels of TNF-α, IL-6, Fas, Bip, Bax, caspase-8, tBid, cleaved caspase-3 caspase-12, cytochrome C, phosphorylation of p38, and ERK in ob/ob mouse hearts, the effects of which with the exception of Bip, Bax, and caspase-12 were alleviated by lenalidomide. Taken together, these data suggest that lenalidomide is protective against obesity-induced cardiomyopathy possibly through antagonism of cytokine/Fas-induced activation of stress signaling and apoptosis.

Cutaneous multicentric Castleman's disease mimicking IgG4-related disease

Castleman's disease, an uncommon lymphoproliferative disorder, can be difficult to differentiate from immunoglobulin (Ig) G4-related disease. The latter is typically characterized by elevated serum IgG4 levels and abundant IgG4-positive cells. However, multicentric Castleman's disease can also have elevated serum IgG4 levels and even fulfill the histological diagnostic criteria for IgG4-related disease. We present a case of cutaneous multicentric Castleman's disease mimicking IgG4-related disease. A 55-year-old Japanese woman developed erythematous and brown plaques on her back. Skin biopsy revealed regressive follicles with interfollicular plasmacytosis, and many plasma cells were positive for IgG4 (mean 263.67±79.19, range 214–355 per high power field). The IgG4-/IgG-positive cell ratios were 35.6%, 36.2%, and 48.4%, respectively, with an average of 40.6%, thus fulfilling the histological diagnostic criteria for IgG4-related disease. Furthermore, serum IgG4 level was significantly elevated (1490mg/dl; normal range: 4.8–105mg/dl). However, laboratory findings of anemia, hypoalbuminemia, polyclonal gammaglobulinemia, high C-reactive protein level, and elevated serum interleukin-6 level were consistent with hyper-IL-6 syndrome. Hence, the diagnosis of cutaneous multicentric Castleman's disease was made. In conclusion, IgG4-related disease cannot be differentiated from hyper-IL-6 syndromes on histology alone. Instead, laboratory analyses are necessary to distinguish between the two diseases.

Correlation between interleukin-6 and ammonia in patients with overt hepatic encephalopathy due to cirrhosis

Previous studies have shown that elevated serum levels of interleukin-6 (IL-6) correlate with the severity of overt hepatic encephalopathy (OHE) in cirrhotic patients. However, the correlation between serum IL-6 levels and plasma ammonia levels in these patients remains unclear. Therefore, the present study investigated this correlation between both variables in cirrhotic patients with OHE. Fifty-five cirrhotic patients with various grades of OHE, 29 cirrhotic patients without OHE, and 30 healthy controls were recruited. Concentrations of plasma ammonia and serum IL-6 were simultaneously measured. In cirrhotic patients with OHE, the severity of OHE, represented by the West Haven criteria, correlated with serum IL-6 levels (r=0.43, P<0.05) and plasma ammonia levels (r=0.59, P<0.05). IL-6 and ammonia were found to be significant independent predictors of OHE severity (P<0.05 for both variables). Furthermore, the severity of liver cirrhosis, determined by Child-Pugh scores, correlated with serum IL-6 levels (r=0.45, P<0.05) and plasma ammonia levels (r=0.68, P<0.05) in these patients. Moreover, there was a significant positive correlation between serum IL-6 levels and plasma ammonia levels (r=0.58, P<0.05) in cirrhotic patients with OHE, but not in patients without OHE (r=0.42, P>0.05) or healthy controls (r=0.27, P>0.05). The correlation between IL-6 and ammonia was independent of infectious precipitating factors. The results of the present study suggest that IL-6 might be involved in the mechanism by which ammonia contributes to the pathogenesis of OHE. There is also evidence of a potential synergistic interaction between proinflammatory cytokines and ammonia in the pathogenesis of OHE.

A case of cutaneous polyarteritis nodosa with elevated serum interleukin-6 levels complicated by leg arterial stenosis and destructive arthropathy of the left ankle

We report a case of a 60-year-old female with cutaneous polyarteritis nodosa (CPN) of the left ankle, accompanied by elevated serum interleukin (IL)-6 levels. Computed tomographic angiography revealed severe narrowing of medium-sized arteries in her left leg. Destructive arthropathy in the left ankle was identified by X-ray and magnetic resonance imaging. This is the first Japanese case of severe CPN complicated by destructive arthropathy. Quantification of serum IL-6 might be useful in diagnosis and evaluation of CPN.

Elevated serum levels of interleukin 21 are associated with disease severity in patients with psoriasis

Psoriasis is an immune disorder involving numerous cytokines. Recent studies have shown that interleukin (IL)-21 plays an important role in a variety of inflammatory and autoimmune diseases. It is highly expressed in psoriatic plaques and promotes the proliferation of epidermis in mice. It seems that IL-21 plays an important role in the pathogenesis of psoriasis. However, whether or not it is elevated in the peripheral blood of patients with psoriasis and is associated with disease severity is unclear. Therefore, our study focuses on serum IL-21 levels and their correlation with disease severity. To detect serum IL-21 levels in patients with psoriasis and investigate the correlation between these and the Psoriasis Area and Severity Index (PASI) scores. Blood samples were collected from patients with plaque psoriasis and from healthy control subjects. Serum IL-21 levels were measured by enzyme-linked immunosorbent assay in 37 patients with psoriasis and 37 healthy controls. The PASI scores of patients with psoriasis and their correlation with serum IL-21 levels were evaluated. Serum IL-21 levels were higher in patients with psoriasis than in healthy controls (P < 0·01). Serum IL-21 levels were positively correlated with PASI scores in the patients with psoriasis (r = 0·471, P < 0·01). Serum IL-21 levels in patients with psoriasis are elevated and positively correlate with PASI scores. These results indicate that IL-21 may play an important role in the pathogenesis of psoriasis.

Polymorphisms of −174G&gt;C and −572G&gt;C in the Interleukin 6 (IL-6) Gene and Coronary Heart Disease Risk: A Meta-Analysis of 27 Research Studies

ObjectiveElevated serum IL-6 level is a risk factor for coronary heart disease (CHD). The −174G>C and −572G>C polymorphisms in the IL-6 gene have previously been shown to modulate IL-6 levels. But the association between the −174G>C and −572G>C polymorphisms and the risk of CHD is still unclear. A meta-analysis of all eligible studies was carried out to clarify the role of IL-6 gene polymorphisms in CHD.Methods and ResultsPubMed, EMBASE, Vip, CNKI and CBM-disc were searched for eligible articles in English and Chinese that were published before October 2010. 27 studies involving 11580 patients with CHD and 17103 controls were included. A meta-analysis was performed for the included articles using the RevMan 5.0 and Stata 10.0 softwares. Overall, the −174C allele was not significantly associated with CHD risk (ORs = 1.04, 95%CI = 0.98 to 1.10) when compared with the −174G allele in the additive model, and meta-analysis under other genetic models (dominant, recessive, CC versus GG, and GC versus GG) also did not reveal any significant association. On the contrary, the −572C allele was associated with a decreased risk of CHD when compared with the −572G allele (ORs = 0.79, 95%CI = 0.68 to 0.93). Furthermore, analyses under the recessive model (ORs = 0.69, 95% = 0.59 to 0.80) and the allele contrast model (genotype of CC versus GG, ORs = 0.49, 95% = 0.35 to 0.70) yielded similar results. However, statistical significance was not found when the meta-analysis was restricted to studies focusing on European populations, studies with large sample size, and cohort studies by using subgroup analysis.ConclusionsThe −174G>C polymorphism in the IL-6 gene is not significantly associated with increased risks of CHD. However, The −572G>C polymorphism may contribute to CHD development. Future investigations with better study design and large number of subjects are needed.

Maternal serum interleukin-6 and its association with clinicopathological infectious morbidity in preterm premature rupture of membranes: a prospective cohort study

Objective: To analyze the association of maternal serum interleukin-6 (IL-6) with fetomaternal outcome in preterm premature rupture of membranes (PPROM). Methods: Serial serum IL-6 levels were measured in 45 women with PPROM at gestation 24–34 weeks. The women were followed till pueperium and fetomaternal outcome as well as the histopathology of the placenta and the umblical cord was studied. The data were analyzed using t test and χ2 test. Results: IL-6 levels ≥ 8 pg/ml were significantly associated with puerperal sepsis and neonatal sepsis. Histological chorioamnionitis and funisitis were demonstrated in 48.8% and 13.3% women respectively and significantly correlated with elevated serum IL-6 levels and fetomaternal infection. A cut-off value of IL-6 of 8 pg/ml was found to correctly diagnose 19 out of 23 patients with infectious morbidity and showed the best sensitivity (82.6%) and specificity (86.3%) as compared to the total leucocycte count (TLC) and C-reactive protein (CRP) in diagnosing infection in PPROM. Conclusion: Maternal serum IL-6 can be used as a biomarker to predict preclinical asymptomatic infection in PPROM with good sensitivity and specificity.

Blockade of Interleukin-6 Receptor Alleviates Disease in Mouse Model of Scleroderma

Activation of fibroblasts by interleukin-6 (IL-6) is implicated in the pathogenesis of scleroderma, suggesting that the inhibition of fibroblast activation may be a promising scleroderma treatment. In this study, we used an IL-6 blocking antibody (Ab) and Il-6 knockout (Il-6KO) mice to examine the role of IL-6 in the bleomycin (BLM)-induced mouse model of scleroderma. BLM was administered to C57BL/6 and Il-6KO mice to induce dermal sclerosis. BLM-treated and control phosphate-buffered saline-treated mice were treated with anti-mouse IL-6 receptor monoclonal Ab (MR16-1). Disease severity was evaluated by measuring dermal thickness and skin hardness, by counting the numbers of α-smooth muscle actin-positive cells and mast cells, and by examining the cutaneous draining lymph nodes. C57BL/6 mice with BLM induced scleroderma had elevated serum IL-6 levels and more severe dermal sclerosis than Il-6KO mice. Weekly administration of MR16-1, but not control Ab, prevented and improved dermal sclerosis, and also attenuated swelling of the draining lymph nodes. MR16-1 suppressed α-smooth muscle actin induction in IL-6-stimulated Il-6KO fibroblasts. Our results indicate that IL-6 contributes to BLM induced dermal sclerosis and that IL-6 receptor-specific monoclonal Ab may improve the symptoms of scleroderma by suppressing fibroblast activation.

Differences in Efficacy and Cytokine Profiles following Echinocandin or Liposomal Amphotericin B Monotherapy or Combination Therapy for Murine Pulmonary or Systemic Aspergillus flavus Infections

Given the recent increase in aspergillosis caused by species other than Aspergillus fumigatus, micafungin, caspofungin, and liposomal amphotericin B (L-AmBi) were investigated as monotherapy or combination therapy for murine systemic or pulmonary Aspergillus flavus infection. Treatment for 3 or 6 days was begun at 24 h (intravenous [i.v.], 2.8 × 10(4) conidia) or 2 h (intranasal, 4.1 × 10(6) to 6.75 × 10(6) conidia) postchallenge as follows: 5 or 10 mg/kg L-AmBi, 10 mg/kg caspofungin, 15 mg/kg micafungin, L-AmBi plus echinocandin, L-AmBi on days 1 to 3 and echinocandin on days 4 to 6, or echinocandin on days 1 to 3 and L-AmBi on days 4 to 6. Mice were monitored for survival, fungal burden, serum or tissue cytokines, and lung histopathology. In the systemic infection, micafungin or caspofungin was more effective than L-AmBi in prolonging survival (P < 0.05), and L-AmBi was associated with significantly elevated serum levels of interleukin-6 (IL-6), macrophage inflammatory protein 1α (MIP-1α), and IL-12 (P < 0.05). In contrast, L-AmBi was significantly more effective than the echinocandins in reducing fungal growth in most tissues (P < 0.05). Concomitant therapies produced significantly enhanced survival, reduction in fungal burden, and low levels of proinflammatory cytokines, while antagonism was seen with some sequential regimens. In comparison, in the pulmonary infection, L-AmBi was significantly better (P < 0.05) than caspofungin or the combination of L-AmBi and caspofungin in prolonging survival and reducing lung fungal burden. Caspofungin stimulated high lung levels of IL-1α, tumor necrosis factor alpha (TNF-α), and IL-6, with extensive tissue damage. In summary, systemic A flavus infection was treated effectively with L-AmBi plus micafungin or caspofungin provided that the drugs were administered concomitantly and not sequentially, while pulmonary A. flavus infection responded well to L-AmBi but not to caspofungin.

Serum Levels of Interleukin-6 and Interleukin-10 in Relation to Depression Scores in Patients with Cardiovascular Risk Factors

It is currently unknown whether elevated cytokine levels in depression are confined to any specific subgroup of depressive patients. In this study, medical out-patients presenting with cardiovascular risk factors (N = 356) were assessed for both cognitive–affective and physical symptoms of depression using the Hospital Anxiety and Depression Scale (HADS) and the Maastricht questionnaire (MQ), respectively. In study participants assigned to the highest (≥21) and lowest (≤5) quartile for the MQ score, serum levels of cytokines were measured. We found highly significant associations between cognitive–affective symptoms of depression and elevated serum levels of interleukin-6 (IL-6; ρ = .231; p = .002) and interleukin-10 (IL-10; ρ = .370; p < .001), respectively. In multiple regression models elevated IL-10 serum concentration was independently related to cognitive–affective symptoms of depression (ρ = .165; p = .002). When all cytokines were included in one model, elevated IL-10 serum concentrations remained a significant predictor for depressive mood (ρ = .157; p = .009). In patients with cardiovascular risk factors and extreme scores for vital exhaustion, elevated serum IL-6 and even more IL-10 concentrations are linked to the presence of depressive mood. Future studies will have to test whether the so far unreported association of IL-10 with depressive mood represents a causal pathway involved in the pathogenesis or in the prognostic effect of depressive mood in cardiac patients.

Elevated Serum Levels of Interleukin-6, Interleukin-1β and Human Chorionic Gonadotropin in Pre-eclampsia

Pre-eclampsia (PE) is a pregnancy-specific syndrome of unknown aetiology. It is believed to involve an inflammatory process. The aim of the study was to investigate and compare the concentrations of two proinflammatory cytokines interleukin-6 (IL-6) and interleukin-1β (IL-1β) and to evaluate the possible interaction between them and human chorionic gonadotropin (hCG) in women with normotensive pregnancy and PE. A prospective case-control study was carried out in 30 women with PE and 30 normotensive controls. Serum IL-1β, IL-6 and hCG levels were determined by enzyme-linked immunosorbent assay (ELISA) and automated immunofluorescent assay, respectively. Serum IL-6, IL-1β and hCG levels were significantly increased in women with PE compared to controls (P < 0.001 for each); however, no correlation was found between IL-6, IL-1β and hCG. Our results highlight the inflammatory origin of PE and reinforce the possible role of hCG in the complex aetiology of its pathogenesis.

The serum level of interleukin-6 in patients with intellectual disability and refractory epilepsy

We aimed to study the influences of active epilepsy and intellectual disability (ID) on the serum interleukin-6 (IL-6) by determining levels in 74 patients with developmental disorder with epilepsy and 63 healthy controls. The patients showed significantly higher IL-6 levels than the controls (4.1±4.5pg/ml vs. 2.1±1.0pg/ml; p<0.001). High seizure frequency and severe intellectual disability emerged as predictors for elevated serum levels of IL-6.

Predisposition for borderline personality disorder with comorbid major depression is associated with that for polycystic ovary syndrome in female Japanese population

Polycystic ovary syndrome (PCOS) is a common lifestyle-related endocrinopathy in women of reproductive age and is associated with several mental health problems. We examined the genotypic distributions of IRS-1 Gly972Arg and CYP11B2 -344T/C, which were previously described as influencing PCOS, and assayed the serum levels of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), in a set of female patients with borderline personality disorder (BPD) with comorbid major depressive disorder (MDD) (n = 50) and age-matched control subjects (n = 100), to investigate the predisposition for BPD with MDD. The results showed that the patients were more frequently IRS-1 972Arg variant allele carriers (P = 0.013; OR 6.68; 95% CI = 1.30–34.43) and homozygous for the CYP11B2 −344C variant allele (P = 0.022; OR = 3.32; 95% CI = 1.18–9.35) than the control subjects. The IL-6 level was significantly higher in the patients than in the controls (P < 0.0001). There was no significant difference in the serum TNF-α level between patients with BPD with MDD and the healthy comparison group (P = 0.5273). In conclusion, the predisposition for BPD with MDD is associated with that for PCOS, in the female Japanese population. An elevated serum IL-6 level is considered to be a possible biomarker of BPD with MDD.

Calcitriol Treatment Attenuates Inflammation and Oxidative Stress in Hemodialysis Patients with Secondary Hyperparathyroidism

Hemodialysis patients with secondary hyperparathyroidism (SHP) suffer from excessive oxidative stress and inflammation. Vitamin D analogues are currently the first line therapy for SHP, but the influence of vitamin D treatment on inflammation and oxidative stress remains unknown. This study investigated the influence of vitamin D therapy on oxidative stress and inflammatory markers in hemodialysis patients with SHP. Twenty-five patients (mean age 58 ± 12 years, 13 males and 12 females) were enrolled in the study to receive calcitriol treatment for 16 weeks. We evaluated changes in the serum biochemical parameters, inflammatory markers [C-reactive protein (CRP) and interleukin-6 (IL-6) levels], serum oxidative stress condition [total antioxidant status (TAS)], and CD4(+) T-lymphocyte intracellular cytokines [interferon γ (IFN-γ) and interleukin-4 (IL-4)] before and at the end of the 16-week calcitriol treatment. Correlations between each of these factors were also studied. All patients with SHP had low serum 1,25-dihydroxyvitamin D(3) levels and elevated serum levels of intact parathyroid hormone (iPTH), CRP and IL-6. Twenty patients (10 males and 10 females) responded to the calcitriol therapy, with significant decrements in serum iPTH. Our results showed that calcitriol can effectively suppress iPTH secretion, reduce inflammatory markers (CRP and IL-6) and oxidative stress. It can also effectively reduce inflammatory cytokine (CD4(+) IFN-γ) and increase anti-inflammatory cytokine (CD4(+) IL-4). Interestingly, significant correlations between CD4(+) IFN-γ levels and serum iPTH levels, as well as between TAS and iPTH levels were noted. Overall, our study has demonstrated calcitriol treatment significantly attenuates inflammation and oxidative stress in hemodialysis patients with SHP.

Multicentric Castleman’s disease representing effusion at initial clinical presentation: clinicopathological study of seven cases

We present here seven cases of idiopathic multicentric Castleman's disease (MCD) showing effusion at the initial clinical presentation. This series includes a high proportion of middle-aged and elderly females (5/7). Various autoantibodies were detected in six cases. Anemia (Hb < 10 g/dl) was detected in four cases, leukocytosis (WBC > 10 × 10(9)/l) in three and thrombycytopenia (<100 × 10(9)/l) in five. Positivity for C-reactive protein or elevated erythrocyte sedimentation rate was recorded in all seven cases. Elevated serum IgG level (>2000 mg/dl) was recorded in only three cases. Elevated serum interleukin-6 level was recorded in all four cases examined. At the onset of disease, four cases were associated with idiopathic thrombocytic purpura. During the course of disease, one case each was diagnosed as systemic sclerosis + Sjögren's syndrome (SJS) and SJS. Histologically, five lesions exhibited a mixed type of Castleman's disease, and one case each exhibited a hyaline-vascular type and plasma cell type. The non-neoplastic nature of the B-lymphocytes was demonstrated by immunohistochemistry and polymerase chain reaction. There were no human herpes type-8 virus-positive cells in any of the seven lesions. Good responsiveness to glucocorticoid therapy has been seen in all six cases treated. From a therapeutic perspective, it is important to discriminate this subtype of MCD.

Interleukin-6 Levels in Tension Headache Patients

Cytokines are pain mediators in neurovascular inflammation. This study examined interleukin 6 (IL-6) levels in the serum of tension-type headache (TTH) patients, to determine if inflammation plays a role in the pathogenesis of this condition. Serum IL-6 levels were studied in 42 patients and 37 healthy controls from the same region. Of the patients, 20 (47.6%) experiencing TTH less than 15 days per month were placed in episodic tension-type headache (ETTH) group, and 22 (52.3%) with TTH more than 15 days per month were placed in chronic tension-type headache (CTTH) group. The IL-6 level was significantly higher in the patients than in the controls. The IL-6 level of CTTH patients was higher than the controls (P<0.01). The IL-6 level was similar between ETTH and CTTH patients. Correlation analysis revealed a positive relationship only between age and IL-6 level in the patients. CTTH and ETTH patients had an elevated serum IL-6 level compared with controls. Therefore, we believe that IL-6 may be involved in pain induction or inflammatory mechanisms in TTH. Furthermore studies of the possible connection between chronicity of headaches and cytokine levels are needed.

Enhanced liver regeneration in IL10 deficient mice after partial hepatectomy via activating hepatocyte STAT3 and stimulating inflammatory response (134.6)

Abstract A series of evidence show that pro-inflammatory cytokines, including tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6), play a critical role in the initiation and progress of liver regeneration. Relatively little is known regarding the role of anti-inflammatory cytokine IL-10 in liver regeneration after partial hepatectomy (PHx). Here, we examined the role of IL-10 in liver regeneration using a model of PHx in several strains of genetically modified mice. IL-10 -/- mice, and IL10-/-STAT3hep-/- double knockout mice in which IL-10 gene was globally disrupted and STAT3 gene was deleted specifically in hepatocytes; and their littermate controls underwent 70% PHx. Liver regeneration was evaluated by BrdU incorporation. After PHx, expression of IL-10 mRNA was significantly elevated after PHx. Compared to wild type mice, IL-10-/- mice had enhanced liver regeneration as determined by measuring hepatocyte proliferation and mitosis with the peak of hepatocyte proliferation occurring 48 hours post PHx. This increased liver regeneration in IL-10-/- mice was associated with elevated serum levels of TNF-alpha and IL-6, and enhanced activation of the IL-6 downstream signal STAT3 in the liver. An additional deletion of STAT3 in hepatocytes reduced liver regeneration in IL-10-/- mice. These findings suggest that IL-10 may negatively regulate liver regeneration via limiting inflammatory cytokine responses and subsequently tempering hepatic STAT3 activation.

Interleukin-6 in bone metastasis and cancer progression

The bone and bone marrow are among the most frequent sites of cancer metastasis. It is estimated that 350,000 patients die with bone metastases annually in the United States. The ability of tumor cells to colonize the bone marrow and invade the bone is the result of close interactions between tumor cells and the bone marrow microenvironment. In this article, we review the contribution of interleukin-6 (IL-6) produced in the bone marrow microenvironment to bone metastasis. This cytokine has a strong pro-tumorigenic activity due to its multiple effects on bone metabolism, tumor cell proliferation and survival, angiogenesis, and inflammation. These effects are mediated by several signaling pathways, in particular the Janus kinase/signal transducer and transcription activator (JAK/STAT-3), Ras/mitogen activated protein kinase (MAPK), and phosphoinositol-3 kinase (PI3K)–protein kinase B/Akt (PkB/Akt), which are activated by IL-6 and amplified in the presence of soluble IL-6 receptor (sIL-6R). Supporting the role of IL-6 in human cancer is the observation of elevated serum levels of IL-6 and sIL-6R in patients with bone metastasis and their association with a poor clinical outcome. Over the last decade several large (monoclonal antibodies) and small (inhibitors of IL-6 mediated signaling) molecules that inhibit IL-6 activity in preclinical models have been developed. Several of these inhibitors are now undergoing phases I and II clinical trials, which will determine their inclusion in the list of effective targeted agents in the fight against cancer.

Anti‐Inflammatory and Anti‐Apoptotic Roles of Endothelial Cell STAT3 in Alcoholic Liver Injury

It is generally believed that the hepatoprotective effect of interleukin-6 (IL-6) is mediated via activation of signal transducer and activator of transcription 3 (STAT3) in hepatocytes. IL-6-deficient mice are more susceptible to alcohol-induced hepatocyte apoptosis and steatosis and elevation of serum alanine transaminase (ALT); however, whereas hepatocyte-specific STAT3 knockout mice are more susceptible to alcohol-induced hepatic steatosis, they have similar hepatocyte apoptosis and serum ALT after alcohol feeding compared with wild-type mice. This suggests that the hepatoprotective effect of IL-6 in alcoholic liver injury may be mediated via activation of STAT3-independent signals in hepatocytes, activation of STAT3 in nonparenchymal cells, or both. We have previously shown that IL-6 also activates STAT3 in sinusoidal endothelial cells (SECs). Thus, the purpose of this study was to investigate whether STAT3 in endothelial cells also plays a protective role in alcoholic liver injury. Wild-type and endothelial cell-specific STAT3 knockout (STAT3(E-/-)) mice were pair-fed and fed ethanol containing diet for 4 weeks. Liver injury and inflammation were determined. Feeding mice with ethanol-containing diet for 4 weeks induced greater hepatic injury (elevation of serum ALT) and liver weight in STAT3(E-/-) mice than wild-type control groups. In addition, ethanol-fed STAT3(E-/-) mice displayed greater hepatic inflammation and substantially elevated serum and hepatic levels of IL-6 and TNF-alpha compared with wild-type mice. Furthermore, ethanol-fed STAT3(E-/-) mice displayed a greater abundance of apoptotic SECs and higher levels of serum hyaluronic acid than wild-type controls. These data suggest that endothelial cell STAT3 plays important dual functions of attenuating hepatic inflammation and SEC death during alcoholic liver injury.

Deletion of Interleukin-6 in Mice With the Dominant Negative Form of Transforming Growth Factor β Receptor II Improves Colitis but Exacerbates Autoimmune Cholangitis

The role of interleukin-6 (IL-6) in autoimmunity attracts attention because of the clinical usage of monoclonal antibodies to IL-6 receptor (IL-6R), designed to block IL-6 pathways. In autoimmune liver disease, activation of the hepatocyte IL-6/STAT3 (signal transducer and activator of transcription 3) pathway is associated with modulating pathology in acute liver failure, in liver regeneration, and in the murine model of concanavalin A-induced liver inflammation. We have reported that mice expressing a dominant negative form of transforming growth factor beta receptor II (dnTGFbetaRII) under control of the CD4 promoter develop both colitis and autoimmune cholangitis with elevated serum levels of IL-6. Based on this observation, we generated IL-6-deficient mice on a dnTGF-betaRII background (dnTGFbetaRII IL-6(-/-)) and examined for the presence of antimitochondrial antibodies, levels of cytokines, histopathology, and immunohistochemistry of liver and colon tissues. As expected, based on reports of the use of anti-IL-6R in inflammatory bowel disease, dnTGFbetaRII IL-6(-/-) mice manifest a dramatic improvement in their inflammatory bowel disease, including reduced diarrhea and significant reduction in intestinal lymphocytic infiltrates. Importantly, however, autoimmune cholangitis in dnTGFbetaRII IL-6(-/-) mice was significantly exacerbated, including elevated inflammatory cytokines, increased numbers of activated T cells, and worsening hepatic pathology. The data from these observations emphasize that there are distinct mechanisms involved in inducing pathology in inflammatory bowel disease compared to autoimmune cholangitis. These data also suggest that patients with inflammatory bowel disease may not be the best candidates for treatment with anti-IL-6R if they have accompanying autoimmune liver disease and emphasize caution for therapeutic use of anti-IL-6R antibody.