Profile of circulating levels of interleukin-1 receptor antagonist and interleukin-6 in colorectal cancer patients

BACKGROUND: Circulating levels of pro-inflammatory cytokines are associated with the disease status of cancer patients. We investigated the profile of circulating levels of interleukin (IL)-6 and its antagonist in colorectal cancer patients. METHODS: Serum concentrations of interkeukin-1 receptor antagonist (IL-1ra) and IL-6 in 80 colorectal cancer patients and tissue concentrations of IL-1ra and IL-6 in 60 primary colorectal cancers and normal colonic mucosas were determined. The serum concentration of immunosuppressive acidic protein (IAP) was also determined. RESULTS: The serum concentrations of IL-1ra and IL-6 in the patients were significantly higher than those in the controls. The serum concentration of IL-1ra in the patients was associated with clinicopathologic factors including tumor size, liver metastasis, lymph node metastasis, vessel involvement, or serum level of carcinoembryonic antigen. Although the serum IL-1ra level increased in keeping with the increase of serum IL-6, the net balance between IL-1ra and IL-6 was significantly lower than that in the controls. The serum IL-1ra to IL-6 ratio decreased in association with the patient's age, the rate of loss of body weight and the serum level of IAP. Although the serum level of IL-6 correlated with the IL-6 concentration in the cancer tissue, the serum level of IL-1ra did not correlate with the IL-1ra concentration in this tissue. CONCLUSIONS: Serum IL-1ra, induced systemically by a marked activation of the IL-6 network in cancer tissue, may be a potent index that evaluates disease progression of colorectal carcinoma. Decreased serum IL-1ra to IL-6 ratio may reflect the deterioration of the systemic anti-inflammatory response that is associated with aging, tumor-related malnutrition, or immunosuppression.     

Increased circulating interleukin-1 and interleukin-6 after intracerebroventricular injection of lipopolysaccharide.

Recently, it was demonstrated that intracerebroventricular (icv) injection of interleukin-1 (IL-1) stimulated circulating interleukin-6 (IL-6) to a greater degree than intravenous (i.v.) injection of IL-1. The goal of this study was to compare the efficacy of lipopolysaccharide (LPS), injected both icv and i.v., on circulating concentrations of IL-1 and IL-6. Both i.v. and icv injection of LPS stimulated plasma levels of IL-1 to a similar degree. However, i.v. injection of LPS was significantly more efficacious than icv injection of LPS in elevating circulating IL-6. These results demonstrate that like i.v. injection of LPS, icv injection of LPS stimulates plasma levels of IL-1 and IL-6. Increases in circulating cytokines during infectious diseases which are limited to the central nervous system may serve to activate peripheral functions of an acute phase response.     

Increased hepatic and circulating interleukin-6 levels in human nonalcoholic steatohepatitis

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2D) are growing public health problems, and are strongly associated. The link between the two conditions remains poorly understood. Hepatic interleukin-6 (IL-6), a major proinflammatory cytokine, expression is increased in animal models of NAFLD, while in mice, selective sustained upregulation of IL-6 in the liver results in systemic insulin resistance. The extent and clinical significance of hepatic IL-6 expression in human NAFLD, as well as potential mechanisms by which steatosis may increase IL-6 production in the liver, have not been examined.
AIMS: To ascertain the occurrence and significance of IL-6 expression in the liver in human NAFLD.
PATIENTS AND METHODS: Plasma was obtained at time of liver biopsy from 50 consecutive patients with suspected NAFLD. Histology was assessed blindly. Hepatic IL-6 expression was assessed by immunohistochemistry, while plasma IL-6 levels were determined by an enzyme-linked immunosorbent assay.
RESULTS: IL-6 expression was markedly increased in the livers of patients with nonalcoholic steatohepatitis (NASH) as compared to patients with simple steatosis ( P < 0.005) or normal biopsies ( P < 0.010), confirming the presence of hepatic IL-6 expression in human NASH. A positive correlation was observed between hepatocyte IL-6 expression and degree of inflammation and stage of fibrosis. Furthermore, liver IL-6 expression positively correlated with plasma IL-6 levels and degree of systemic insulin resistance. Culture of liver cells with saturated, but not mono- or polyunsaturated, FFA resulted in a significant increase in IL-6 messenger RNA (mRNA) and protein expression.
CONCLUSION: Collectively, these data suggest that increased hepatic IL-6 production may play an important role in NASH development, as well as in systemic insulin resistance and diabetes.     

Renal cancer: bone metastases, immunotherapy and interleukin-6]

In renal cell carcinoma, bone metastases remain a major medical challenge because they are refractory to the antiproliferative effects of immunotherapy. We critically review the biological and clinical data which implicate interleukin-6 in the tumor growth, the pathogenesis of the bone metastases and the response to immunotherapy.     

The effect of the interleukin-6 c/g-174 polymorphism and circulating interleukin-6 on fibrinogen plasma levels

BACKGROUND AND OBJECTIVES: C-reactive protein (C-RP) levels correlate with fibrinogen values and are predictive of coronary artery disease. Interleukin-6 (IL-6) strongly regulates the production of C-RP. A polymorphism (C/G-174) within the IL-6 gene has been shown to affect IL-6 gene expression and plasma concentrations. DESIGN AND METHODS: In 598 asymptomatic employees of a hospital in Southern Italy, we investigated the association between IL-6 C/G-174 gene variants and plasma fibrinogen levels. RESULTS: Subjects with IL-6 plasma levels >2.0 pg/mL had a higher body mass index (BMI) (24.5+/-1.2) than subjects with IL-6 levels below this cut-off value (23.7+/-1.2; p =0.005). No association was found with sex, cigarette smoking, or alcohol consumption (p always>0.05). When the whole sample was analyzed according to the IL-6 C/G-174 polymorphism, there was no difference with respect to age, sex, alcohol consumption, cigarette smoking, total cholesterol, triglycerides, and body mass index. Median plasma fibrinogen levels, as well as carriers of plasma levels of IL-6 >2.0 pg/mL and C-RP >0.33 mg/L, were similar among subjects with different IL-6 genotypes. Similarly, no difference was observed when only carriers of plasma levels of IL-6 >2.0 pg/mL were analyzed, whereas in those with C-RP >0.33 mg/L IL-6 GG carriers had significantly lower plasma fibrinogen levels. INTERPRETATION AND CONCLUSIONS: The investigation of the IL-6 C/G-174 polymorphism does not seem to be a useful tool for predicting raised plasma fibrinogen levels.     

Healthy centenarians show high levels of circulating interleukin-22 (IL-22)

Aging is characterized by a progressive alteration of homeostatic mechanisms modulated by environmental and genetic factors. It is associated with a pro-inflammatory status. In centenarians, an increase of pro-inflammatory cytokine production balanced by anti-inflammatory immune response that would promote longevity is observed. Cytokine dysregulation is believed to play a key role in the proposed remodeling of the immune-inflammatory responses accompanying old age. IL-22 is a pro-inflammatory cytokine belonging to the IL-10 family and represents an important effector molecule of activated T helper (Th)-22, Th-1, and Th-17 cells. We recruited 17 healthy centenarians (4 males, 13 females, range 100-105 years). All ultralongeval subjects were living at home or in a nursing home. Sixteen healthy, sex-matched individuals (4 males, 12 females, range 60-95 years) were also recruited as controls. Centenarians displayed significantly higher circulating IL-22 levels compared to control population (45.7±66.9 pg/ml versus 11.1±6.5 pg/ml; p=0.031). It's well known that IL-22 is a pro-inflammatory cytokine produced by activated T lymphocytes and NK cells. IL-22 stimulates the production of acute phase reactants and promotes the antimicrobial defense. The results of the present study show, for the first time, that there is an increase of IL-22 in healthy centenarians. This pro-inflammatory condition probably is protective against infection, promoting the longevity of these subjects.     

Adoptive immunotherapy with high-dose interleukin-2: kinetics of circulating progenitors correlate with interleukin-6, granulocyte colony-stimulating factor level.

Immunotherapy with interleukin-2 (IL-2) and lymphokine-activated killer (LAK) cells results in significant tumor regression in patients with advanced cancer. We have investigated the kinetics of circulating erythroid (BFU-E) and granulocytic-macrophage (CFU-GM) progenitors after IL-2 therapy in 11 cancer patients, mainly affected by metastatic melanoma and renal cell carcinoma. Administration of IL-2 from day 1 through day 5 constantly induced a dramatic decrease of the number of circulating BFU-E and CFU-GM, which then showed a striking rebound (up to values fourfold and sevenfold higher, respectively, than the pretherapy levels) on discontinuation of IL-2, ie, from day 5 through day 10. A similar kinetic pattern was observed during and after the second cycle of IL-2 administration. 3[H]-thymidine killing experiments showed that the cycling activity of the progenitors was virtually unmodified in the rebound phases. To explore the mechanism(s) underlying this kinetic pattern, we have analyzed the plasma concentration of several hematopoietic growth factors, including IL-1 beta, IL-3, IL-4, IL-6, granulocyte-macrophage colony-stimulating factor (GM-CSF), G-CSF, and erythropoietin (Ep). No modifications in the levels of IL-3, GM-CSF, or IL-1 beta were observed, whereas a pronounced increase of IL-6 and G-CSF concentration was monitored, starting at day 3 and peaking at day 5 of treatment (a parallel, but modest, increase of Ep level was also observed). The elevation of IL-6 and G-CSF concentration is directly correlated with and may, at least in part, underlie the subsequent rebound of circulating hematopoietic progenitors. Furthermore, the increase in IL-4 level observed at day 10 of therapy may mediate the eosinophilia gradually starting at this stage of treatment.     

High circulating concentrations of interleukin-6 in active Crohn''s disease but not ulcerative colitis.

Peripheral venous plasma concentrations of interleukin-6 were studied in 21 patients with active Crohn's disease, 20 patients with ulcerative colitis, and 16 control subjects. Interleukin-6 was detected in the plasma of 18 of 21 patients with Crohn's disease (median 47 (range less than 20-250) pg/ml) but in only two with ulcerative colitis and two control subjects. In the patients with Crohn's disease there was a significant negative correlation between the plasma interleukin-6 and the serum albumin concentrations. In eight patients with Crohn's disease and five patients with ulcerative colitis undergoing resection plasma from peripheral circulation and mesenteric vein draining diseased intestine was studied. Interleukin-6 was detected in seven of eight peripheral and mesenteric samples from the patients with Crohn's disease but was not detected in any of the samples from the patients with ulcerative colitis. There was no significant difference between mesenteric and peripheral samples in the concentrations of interleukin-6.     

Association between high interleukin-6 levels and adverse outcome after autologous haemopoietic stem cell transplantation.

We studied interleukin-6 (IL-6) levels on the day of transplantation in 31 patients undergoing autologous haemopoietic stem cell transplantation (SCT) (either peripheral blood stem cell transplantation (PBSCT) or bone marrow transplantation (BMT)) for neoplastic diseases to determine if there was a relationship between IL-6 level and rate of haemopoietic recovery, length of stay in hospital, and survival. There was no apparent delay in post-transplant recovery associated with elevated IL-6 levels. However, increased values of IL-6 tended to be associated with an increased length of stay in hospital (P = 0.083). There was a highly significant adverse association between higher IL-6 levels and survival following transplantation (P = 0.0001). This association remained significant (P = 0.013) in the uniform subgroup of patients with malignant lymphoma with chemosensitive disease who had undergone BMT (that is, excluding patients who had undergone PBSCT) (n = 13). Knowledge of IL-6 levels on the day of transplant has the potential to provide valuable prognostic information in patients undergoing autologous haemopoietic SCT.     

The oxygen stress index and levels of circulating interleukin-10 and interleukin-6 in patients with chronic heart failure

OBJECTIVES: We sought to study circulating levels of pro- and anti-inflammatory cytokines together with the oxygen stress index in patients with chronic heart failure (CHF). BACKGROUND: Patients with CHF exhibit elevated levels of inflammatory and anti-inflammatory cytokines but the relative level of these cytokines with the oxygen stress index have not been reported. METHODS: Twenty-two patients with CHF and 10 control subjects were studied. Plasma levels of IL-6 and IL-10 were determined and the oxygen stress index was evaluated by urine 8-iso-PGF2alpha estimations. RESULTS: Plasma levels of IL-6 and IL-10 in CHF patients were significantly higher than those observed in the control subjects. Patients with more advanced disease (higher NYHA class) showed higher concentrations of IL-10 and IL-6 than those with less serious disease. 8-iso-PGF2alpha urine concentration (and therefore the oxygen stress index) was significantly higher in patients with CHF in comparison with control subjects. IL-6 plasma levels, but not IL-10 concentrations, correlated significantly with 8-iso-PGF2alpha levels in urine. CONCLUSIONS: Inflammatory and anti-inflammatory cytokine levels, as well as the oxidative stress index, are increased in patients with chronic heart failure. Inflammatory cytokine IL-6, but not anti-inflammatory cytokine Il-10, levels correlated significantly with the oxygen stress index.     

Alcohol modulates circulating levels of interleukin-6 and monocyte chemoattractant protein-1 in chronic pancreatitis

BACKGROUND: Cytokines are markers of acute pancreatic inflammation and essential for distant organ injury, but they also stimulate pancreatic fibrogenesis and are thus involved in the progression from acute pancreatitis to chronic pancreatic injury and fibrosis. The aim of this study was to evaluate the circulating levels of IL-6, MCP-1, TGF-beta1, IGF-1 and IGFBP-3 in patients with alcoholic chronic pancreatitis (CP). METHODS: Twelve male patients with severe CP and 11 matched controls ingested 40 g alcohol. Plasma cytokine concentrations were measured for 24 h and assessed by sandwich ELISA techniques. RESULTS: IL-6 was higher in CP at fasting and 1, 4 and 24 h after alcohol intake (P < 0.04), and a significantly greater rise was found at 1 h compared to pre-stimulatory conditions and controls (P < 0.01). MCP-1 plasma levels in CP were significantly decreased at I h (P < 0.01) and 4 h (P < 0.001) compared to pre-stimulatory levels and controls, and a variance analysis showed significantly (P < 0.001) lower post-stimulatory levels at 1 h and 4 h both in CP and in controls. Alcohol consumption (40 g), however, did not influence plasma levels of TGF-1beta, IGF-I or IGFBP-3 in either of the two groups at the time frame applied. CONCLUSIONS: Acute alcohol intake induces a rise in the plasma levels of IL-6 in CP as compared to controls. The low circulating concentrations of MCP-1 1 and 4 h following alcohol consumption might possibly reflect that this mediator acts locally via autocrine mechanisms.     

Plasma visfatin levels are positively associated with circulating interleukin-6 in apparently healthy Korean women

Even though visfatin has been suggested as a proinflammatory adipokine, there are few studies of the relationship between plasma visfatin concentrations and proinflammatory markers in the nondiabetic population. We showed that plasma visfatin concentrations were positively associated with circulating interleukin-6 levels and diastolic blood pressure independent of obesity in nondiabetic healthy Korean women. These results suggest that circulating visfatin may be related with some proinflammatory condition even in a nondiabetic state.     

Soluble interleukin-6 receptors in inflammatory bowel disease: relation to circulating interleukin-6.

The in vivo appearance of soluble interleukin (IL)-6 receptor (sIL-6R) in serum from patients with inflammatory bowel disease was examined using an enzyme linked immunosorbent assay (ELISA). The serum sIL-6R concentrations in patients with active disease (ulcerative colitis, 148.4 (5.1); Crohn's disease, 142.3 (9.3) ng/ml; mean (SEM)) were significantly raised compared with those in patients with inactive disease (ulcerative colitis, 116.2 (7.2); Crohn's disease, 114.3 (7.1) ng/ml), some other type of colitis (104.8 (11.6) ng/ml), or in normal subjects (107.3 (2.4) ng/ml). These differences were also seen in paired samples examined during both active and inactive phases. Additionally, serum sIL-6R and IL-6 concentrations correlated significantly with C-reactive protein levels in both ulcerative colitis and Crohn's disease patients (r = 0.23 and 0.56, respectively; p < 0.05 for both). Furthermore, gel filtration analysis of serum from these patients showed two major peaks of immunoreactive IL-6-one peak corresponding to free IL-6 and another peak to sIL-6R-bound IL-6-this was further confirmed by a luminescence sandwich ELISA. These results, together with its in vitro effects, indicate that natural sIL-6R may function as a powerful enhancer of the IL-6-dependent immune processes observed in inflammatory bowel disease.     

Raised circulating interleukin-18 levels in reactive AA-amyloidosis.

OBJECTIVE: To study the circulating levels of interleukin-18 (IL-18), a proinflammtory cytokine implicated in the T helper I response, in patients with rheumatoid arthrtitis (RA) with or without amyloidosis. METHODS: Plasma IL-18 levels were studied by enzyme-linked immusorbent assay in 55 RA patients with reactive amyloidosis and in 55 RA patients without amyloidosis matched with respect to age, sex, seropositivity, disease duration and inflammatory activity, as well as in 55 healthy control subjects. RESULTS: Plasma IL-18 levels were significantly elevated in RA patients as compared with control subjects. Those RA patients who had amyloid had significantly higher circulating level of IL-18 than those without amyloid (418.1 +/- 32.1 ng/l versus 317.0 +/- 21.3 ng/l, P<0.02). This difference was not due to differences in inflammatory activity, nor was it related to renalfunction. CONCLUSION: RA is associated with increased levels of plasma IL-18, the levels being significantly higher in patients with amyloid than in those without amyloid The increased level in the amyloidosis patients may reflect the interaction ofamyloid with cellular meatbolic pathways or, possibly, suggest a direct role of IL-18 in amyloidogenesis.     

Staphylococcus aureus infection of mouse or human osteoblasts induces high levels of interleukin-6 and interleukin-12 production

Staphylococcus aureus is the principal causative agent of the inflammatory bone disease osteomyelitis. Unfortunately, the pathogenesis of this often chronic infection is poorly understood and is complicated by the recent observation that bone-forming osteoblasts can harbor S. aureus. Such an infection presents a significant challenge for the host immune response, because osteoblasts are not known to initiate protective cell-mediated immune responses. Cultured mouse and human osteoblasts infected with S. aureus were found to express high levels of interleukin (IL)-6 and IL-12p75, on the basis of complementary investigations demonstrating both S. aureus-induced up-regulation of expression of IL-6 and IL-12p40 mRNA and secretion of IL-6 and IL-12p75 by these cells. Additionally, a quantitative bioassay demonstrated that IL-12p75 secreted after infection was biologically active. These studies are the first to demonstrate induced IL-12p75 expression by osteoblasts and suggest a previously unrecognized role for osteoblasts in initiating immune responses after S. aureus infection.     

Antigen specific active immunotherapy: lessons from the first decade

Malignant melanoma is a tumour with a steeply rising incidence and scarce therapeutic options once metastatic. Approximately 1200 new cases are reported yearly in Switzerland with roughly 220 deaths/year. An important particularity of melanoma is its immunogenicity, which has long been recognized and investigated using various clinical immunization protocols in the last fifty years. The year 1991, when the first melanoma associated antigen was molecularly characterized, represents a turning point in the quest for a melanoma immunotherapy. This opened the era of antigen specific active immunotherapy. Many clinical centres have developed immunization strategies in an adjuvant setting for the treatment of metastatic melanoma. The molecular characterization of melanoma associated antigens allows a fine monitoring of the elicited immune response. Certain clinical responses to these efforts have been seen and a phase of reflection is now ongoing, with refinements and further sophistication taking place in order to fully realize the potential of antigen specific active immunotherapy. Here we provide an overview of the technologies used and of the progress reported in melanoma immunotherapy since 1991. Furthermore, we propose some research lines in basic and translational research aimed at improving our capacity to induce specific and clinically relevant immune responses against melanoma.     

红细胞TF抗原用于老年恶性肿瘤病人的特异性主动免疫治疗

目的　使用一种癌症疫苗探讨其对老年癌症患者的疗效。方法　用神经氨酸酶处理红细胞，使其表面隐匿的 Ｔ Ｆ抗原暴露，作为一种癌症疫苗对癌症患者进行特异性主动免疫治疗。结果　所有病人在治疗后其行为状态明显改善（ Ｐ＜ ０００１）；淋巴细胞转化能力增强，白细胞介素Ⅱ活性增加（均 Ｐ＜ ００１），这种改变在晚期肿瘤病人（ Ｔ Ｎ Ｍ 分期为Ⅲ、Ⅳ期）表现得尤为显著。结论　用自身红细胞中提取的 Ｔ Ｆ 抗原制成的癌症疫苗能控制肿瘤生长，改善老年癌症病人的行为状态，提高生活质量。     

Serum interleukin-6 and hepatocyte growth factor levels in patients after hepatectomy

BACKGROUND/AIMS: To examine whether serum hepatocyte growth factor and interleukin-6 levels are early parameters of postoperative liver dysfunction after hepatectomy. METHODOLOGY: The serum levels of hepatocyte growth factor and interleukin-6 were measured in 16 hepatectomized patients on the day of surgery (before surgery, immediately after hepatectomy, after completion of surgery) and on postoperative days 1, 3, and 5. Serum liver function tests were determined for 14 days after surgery and their results were correlated with serum interleukin-6 and hepatocyte growth factor levels. RESULTS: Serum interleukin-6 and hepatocyte growth factor levels were elevated after surgery and these values were higher in patients who underwent hepatectomy greater than lobectomy in magnitude. The mean maximum value of interleukin-6 appeared on day 0 and was earlier than that of hepatocyte growth factor, which was found on day 1. Serum total bilirubin and alanine aminotransferase levels reached the maximum within 5 days after surgery. Multiple regression analysis showed that serum levels of interleukin-6 and hepatocyte growth factor on day 0 after surgery were significantly correlated with the postoperative maximum total bilirubin level (P < 0.0001). The maximum interleukin-6 level but not hepatocyte growth factor significantly correlated with the postoperative maximum bilirubin level (P < 0.02). CONCLUSIONS: Both the serum interleukin-6 and hepatocyte growth factor levels are likely early indicators of postoperative liver dysfunction in patients after hepatectomy.