Infusion Of Interleukin-2 Research Articles

Petar Alaupovic

Petar Alaupovic, an internationally renowned biochemist and lipidologist, died on January 30, 2014, in Oklahoma City at the age of 91 years. Dr Alaupovic was a founder of the modern field of lipoproteins whose ideas continue to have an impact on its development. He performed research and taught at Oklahoma Medical Research Foundation since 1960. In 1964, Dr Alaupovic, known to his colleagues as Dr A or Pierre, proposed a revolutionary new classification system for lipoproteins. Until that time, the classification of lipoproteins focused on the physical properties of lipoproteins, emphasizing the lipid component and the size of the lipoprotein particle. However, Dr Alaupovic considered the protein part to have great biological importance that directed every step in the metabolism of lipoproteins and determined their effects on atherosclerosis. When he began his research on lipoproteins, there were considered to be just 2 apolipoproteins, apolipoprotein B and apolipoprotein A. Using immunologic and protein chemistry techniques, he isolated and characterized several additional apolipoproteins associated with lipoproteins. He proposed the ABC nomenclature for apolipoproteins, which initially included apolipoproteins A-I, A-II, B, C-I, C-II, C-III, D, and E. Most important to the subsequent progress in the field of lipoprotein, he subdivided the major lipoprotein classes, apolipoprotein A-I …

Platelet Activation and Platelet-leukocyte Aggregation Elicited in Experimental Colitis Are Mediated by Interleukin-6

There is growing evidence for an interdependence of inflammation, coagulation, and thrombosis in acute and chronic inflammatory diseases. Inflammatory bowel diseases (IBD) are associated with a hypercoagulable state and an increased risk of thromboembolism. Although the IBD-associated prothrombogenic state has been linked to the inflammatory response, the mediators that link these 2 conditions remain unclear. Recent evidence suggests that interleukin-6 (IL-6) may be important in this regard. The objective of this study was to more fully define the contribution of IL-6 to the altered platelet function that occurs during experimental colitis. The number of immature and mature platelets, activated platelets, and platelet-leukocyte aggregates were measured in wild-type and IL-6 mice with dextran sodium sulfate (DSS)-induced colonic inflammation. DSS treatment of WT mice was associated with significant increases in the number of both immature and mature platelets, activated platelets, and platelet-leukocyte aggregates. These platelet responses to DSS were not observed in IL-6 mice. Chronic IL-6 infusion (through an Alzet pump) in WT mice reproduced all of the platelet abnormalities observed in DSS-colitic mice. IL-6-infused mice also exhibited an acceleration of thrombus formation in arterioles, similar to DSS. These findings implicate IL-6 in the platelet activation and enhanced platelet-leukocyte aggregate formation associated with experimental colitis, and support a role for this cytokine as a mediator of the enhanced thrombogenesis in IBD.

Effect of IL-6 on the insulin sensitivity in patients with type 2 diabetes

Elevated interleukin-6 (IL-6) levels are associated with type 2 diabetes, but its role in glucose metabolism is controversial. We investigated the effect of IL-6 on insulin-stimulated glucose metabolism in type 2 diabetes patients and hypothesized that an acute, moderate IL-6 elevation would increase the insulin-mediated glucose uptake. Men with type 2 diabetes not treated with insulin [n = 9, age 54.9 ± 9.7 (mean ± SD) yr, body mass index 34.8 ± 6.1 kg/m(2), HbA1c 7.0 ± 1.0%] received continuous intravenous infusion with either recombinant human IL-6 (rhIL-6) or placebo. After 1 h with placebo or rhIL-6, a 3-h hyperinsulinemic-isoglycemic clamp was initiated. Whole body glucose metabolism was measured using stable isotope-labeled tracers. Signal transducer and activator of transcription 3 (STAT3) phosphorylation and suppressor of cytokine signaling 3 (SOCS3) expression were measured in muscle biopsies. Whole body energy expenditure was measured using indirect calorimetry. In response to the infusion of rhIL-6, circulating levels of IL-6 (P < 0.001), neutrophils (P < 0.001), and cortisol (P < 0.001) increased while lymphocytes decreased (P < 0.01). However, IL-6 infusion did not change glucose infusion rate, rate of appearance, or rate of disappearance during the clamp. While IL-6 enhanced phosphorylation of STAT3 in skeletal muscle (P = 0.041), the expression of SOCS3 remained unchanged. Whole body oxygen uptake (P < 0.01) and expired carbon dioxide (P < 0.01) increased during rhIL-6 infusion. In summary, although IL-6 induced local and systemic responses, the insulin-stimulated glucose uptake was not affected. While different contributing factors may be involved, our results are in contrast to our hypothesis and previous findings in young, healthy men.

Activity of Outpatient Intravenous Interleukin-2 and Famotidine in Metastatic Clear Cell Kidney Cancer

Outpatient daily intravenous infusions of interleukin-2 (IL-2) have been developed to maintain anticancer activity and decrease toxicity of this agent against kidney cancer. Lymphokine activated killer cell (LAK) numbers are increased with these IL-2 schedules. Famotidine may enhance the LAK activity by increasing IL-2 internalization by the IL-2 receptor on lymphocytes. Fifteen patients with metastatic clear cell kidney cancer received IL-2 18 million IU/M² intravenously over 15-30 minutes preceded by famotidine 20 mg IV daily for 3 days for 6 consecutive weeks as outpatients. Cycles were repeated every 8 weeks. Patient characteristics were seven males/eight females, median age 59 (range: 28-70), median Eastern Cooperative Oncology Group (ECOG) performance status-1; common metastatic sites were lungs (14), lymph nodes (9), liver (4), bone (4), and pancreas (4). Prior systemic therapies were oral tyrosine kinase inhibitor (8), IL-2 (6), and mTor inhibitor (2). Most common toxicities were rigors, arthralgia/myalgia, nausea/emesis, fever, and hypotension. All episodes of hypotension were reversible with intravenous fluid. No patients required hospitalization due to toxicity. One complete response (7%) and four partial responses (26%) were seen (total response rate=33%; 95% confidence interval: 15%-59%). Responses occurred in the lungs, liver, lymph nodes, and bone. Outpatient intravenous IL-2 with famotidine has activity in metastatic clear cell kidney cancer.

Activity of dose-dense outpatient intravenous Interleukin-2 preceded by famotidine in metastatic clear cell cancer of the kidney

Daily short intravenous infusions of Interleukin-2 (IL-2) have been developed to decrease toxicity while maintaining anticancer activity of this agent against kidney cancer. Such IL-2 schedules have previously been shown to increase Lymphokine Activated Killer cell (LAK) numbers (Quan) and LAK activity (Mitchell). Famotidine may increase LAK activity by increasing Interleukin-2 internalization by the IL-2 receptor on lymphocytes (Tsunoda). We treated 15 patients with metastatic clear cell kidney cancer using IL-2 18 Million IU/M2 intravenously over 15-30 minutes preceded by famotidine 20 mg IV daily for 3 days for 6 consecutive weeks on an outpatient basis. Cycles were repeated every 8 weeks until disease progression. Patient characteristics: 7 males/8 females, median age-59 (range: 28-70), median ECOG performance status-1; common metastatic sites: lungs (14), lymph nodes (9), liver (4), bone (4), and pancreas (4). Prior systemic therapy: oral TKI (8), Interleukin-2 (6), mTor inhibitor (2), no prior (3). Prior nephrectomy (9). Most common toxicities were rigors (13), arthralgia/myalgia (12), nausea/emesis (11), fever (11), hypotension (11), and constipation (8). All episodes of hypotension were transient and alleviated with outpatient intravenous fluid. No patients have required hospitalization due to toxicity of therapy. There have been no treatment-related deaths. One complete response (7%) (in lungs lasting 13 months) and four partial responses (26%) have been seen (total response rate =33%; 95% CI:15-59%). Responses have occurred in lungs, liver, lymph nodes, and bone. Median response duration = 5 months (2-13). Median survival = 13.75 months (3-41 months). Two patients are alive at 35.7+ and 35.2+ months. Dose-dense outpatient intravenous Interleukin-2 preceded by famotidine has activity in metastatic clear cell kidney cancer.

Upregulation of skeletal muscle inflammatory genes links inflammation with insulin resistance in women with the metabolic syndrome

The metabolic syndrome, a combination of interrelated metabolic risk factors, is associated with insulin resistance and promotes the development of cardiovascular diseases and type 2 diabetes mellitus. There is a close link between inflammation and metabolic disease, but the responsible mechanisms remain elusive. The aim of this study was to identify differentially expressed genes in insulin-resistant skeletal muscle tissue of women with the metabolic syndrome compared with healthy control women. Women with the metabolic syndrome (n = 19) and healthy control women (n = 20) were extensively phenotyped, insulin sensitivity was measured using a hyperinsulinaemic euglycaemic clamp, and a skeletal muscle biopsy was obtained. Gene expression levels were compared between the two groups by microarrays. The upregulated genes in skeletal muscle of the women with the metabolic syndrome were primarily enriched for inflammatory response-associated genes. The three most significantly upregulated of this group, interleukin 6 receptor (IL6R), histone deacetylase 9 (HDAC9) and CD97 molecule (CD97), were significantly correlated with insulin resistance. Taken together, these findings suggest an important role for a number of inflammatory-related genes in the development of skeletal muscle insulin resistance.

Outpatient Intravenous Interleukin-2 with Famotidine Has Activity in Metastatic Melanoma

Daily short intravenous interleukin-2 (IL-2) infusions have been developed to decrease toxicity while maintaining the anticancer activity of this agent against melanoma. Such IL-2 schedules have previously been shown to promote lymphokine-activated killer cell (LAK) activity. Famotidine may increase LAK activity by increasing IL-2 internalization by the IL-2 receptor on lymphocytes. Twenty-one patients with metastatic melanoma were treated with IL-2 18 million IU/m² intravenously (i.v.) over 15-30 minutes and famotidine 20 mg i.v. daily for 3 days for 6 consecutive weeks on an outpatient basis. Cycles were repeated every 8 weeks. 13 males/8 females, median age, 51 (range: 26-79), and median Eastern Cooperative Oncology Group performance status, 1; common metastatic sites: lymph nodes (16), lungs (14), subcutaneous (8), liver (7), and bone (7). Prior systemic therapy: chemotherapy (7); IL-2 (7); and interferon (5). Most common toxicities were myalgia/arthralgia, rigors, nausea/emesis, and mild elevation of liver function tests. No patients required hospitalization for toxicity of therapy. One patient (5%) has had a complete response (ongoing at 29+ months), while 4 other patients (19%) had partial responses (total response rate: 24%; 95% confidence interval: 9%-48%). Responses occurred in lung, spleen, bones, lymph nodes, and subcutaneous sites. Median response duration=20+ months. Outpatient intravenous IL-2 and famotidine has activity in melanoma.

Activated STAT5 Promotes Long-Lived Cytotoxic CD8+ T Cells That Induce Regression of Autochthonous Melanoma

Immunotherapy based on adoptive transfer of tumor antigen-specific CD8(+) T cell (TC) is generally limited by poor in vivo expansion and tumor infiltration. In this study, we report that activated STAT5 transcription factors (STAT5CA) confer high efficiency on CD8(+) effector T cells (eTC) for host colonization after adoptive transfer. Engineered expression of STAT5CA in antigen-experienced TCs with poor replicative potential was also sufficient to convert them into long-lived antigen-responsive eTCs. In transplanted mastocytoma- or melanoma-bearing hosts, STAT5CA greatly enhanced the ability of eTCs to accumulate in tumors, become activated by tumor antigens, and to express the cytolytic factor granzyme B. Taken together, these properties contributed to an increase in tumor regression by STAT5CA-transduced, as compared with untransduced, TCs including when the latter control cells were combined with infusion of interleukin (IL)-2/anti-IL-2 complexes. In tumors arising in the autochthonous TiRP transgenic model of melanoma associated with systemic chronic inflammation, endogenous CD8(+) TCs were nonfunctional. In this setting, adoptive transfer of STAT5CA-transduced TCs produced superior antitumor effects compared with nontransduced TCs. Our findings imply that STAT5CA expression can render TCs resistant to the immunosuppressive environment of melanoma tumors, enhancing their ability to home to tumors and to maintain high granzyme B expression, as well as their capacity to stimulate granzyme B expression in endogenous TCs.

Cytokines

This review highlights the role of cytokines, in particular tumour necrosis factor alpha (TNF-α) and interleukin-6 (IL-6), in relation to the nature of human in-vivo muscle wasting in disease. Infusion of human TNF-α and IL-6 in healthy individuals, acutely raises TNF-α and IL-6 to moderate levels, has only identified IL-6 as a potent cytokine, decreasing systemic amino acid levels and muscle protein metabolism. The marked decrease in circulatory and muscle amino acid concentrations was observed with a concomitant reduction in both the rates of muscle protein synthesis and breakdown, that is, reduced turnover with a minor increase in net muscle degradation. Very similar observations have been made in models of acute inflammation, induced by high-dose endotoxin injection. However, these changes were suggested not to be attributed to a direct effect of IL-6 on the regulation of muscle protein metabolism but indirectly via IL-6 reducing amino acid availability. Recent studies suggest that the best described cytokines TNF-α and IL-6 are unlikely to be the major direct mediators of muscle protein loss in inflammatory diseases. However, these cytokines can initiate important changes in secondary mediators and/or clinical complications that need correction therapies causing muscle wasting. Moreover, the general view from animal work is that in muscle wasting the rate of muscle protein synthesis is decreased and the rate of breakdown is increased. However, this does not seem applicable for inflammatory diseases or human models of sepsis, in which the enhanced imbalance between these two processes is observed within an enhanced, normal or reduced muscle protein turnover.

Effects of intrahippocampal infusion of interleukin-6 on passive avoidance and nitrite and prostaglandin levels in the hippocampus in rats.

Bilateral infusion of interleukin-6 (IL-6) 80 ng into the hippocampus has been shown to impair retention of a step-through passive avoidance task via shortening the step-through latency in testing. This infusion with IL-6 also increased the levels of nitrite and 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) in rat hippocampus. In addition, intraperitoneal injection of NG-nitro-L-arginine (CAS 2149-70-4) 100 mg/kg for 5 days improved the retention impairment induced by IL-6 and meanwhile antagonized the increase in nitrite levels. Furthermore, intraperitoneal injection with indometacin (CAS 53-86-1) 10 mg/kg daily for 5 days reduced the IL-6-induced increase in 6-keto-PGF1 alpha levels. These results indicate that IL-6 impairs retention of passive avoidance probably via the overproduction of nitric oxide (NO) and suggest that IL-6 may possess an inducible effect on NO synthase and cyclo-oxygenase in the hippocampus. These findings support the hypothesis that central IL-6 participates in the pathogenesis of Alzheimer's disease, and the overproduction of nitric oxide in the brain may partially mediate the amnesic effect of IL-6.

Is Radiotherapy An Effective Treatment Option for Recurrent Metastatic Malignant Melanoma? a Case Report of Short-Course, Large-Fraction Radiation and a Literature Review

Malignant melanoma is regarded to be radiation resistant. A case of recurrent malignant melanoma with in-transit metastasis treated with short-course, high-fraction palliative radiation is presented to illustrate the effectiveness of radiotherapy. An 80-year-old woman initially treated surgically for a primary malignant melanoma of the left lower leg presented with multiple in-transit metastases. Palliative radiation was offered to treat two fungating in-transit masses that were resistant to treatments of isolated limb infusion and intralesional interleukin-2. Treatment consisted of short-course, high-fraction radiation with 800 cGy fractions given over three weeks on days 0, 7 and 21, for a total dose of 2400 cGy. She experienced a complete response that was maintained for six months. Radiation is an effective treatment option for palliation of recurrent malignant melanoma. Complete response is possible even with short-course, high-fraction radiation.

Hypertension in response to IL-6 during pregnancy: role of AT1-receptor activation

BACKGROUND: Increases in interleukin 6 (IL-6) and agonistic autoantibodies to the angiotensin II type 1 receptor (AT1-AA) are proposed to be important links between placental ischemia and hypertension in preeclampsia. METHODS: The purpose of this study was to determine whether IL-6 (5 ng/day), infused into normal pregnant (NP) rats, increased mean arterial pressure (MAP) and AT1-AA. MAP was analyzed in the presence and absence of an angiotensin type 1 receptor (AT1R) antagonist, losartan, L. RESULTS: MAP and AT1-AA increased from 102 ± 2 to 118 ± 4 mmHg and 0.7 ± 0.3 NP to 14.1 ± 1.4 chronotropic units with chronic IL-6 infusion. MAP responses to IL-6 were abolished in losartan pretreated rats (85 ± 4 in NP + L vs 85 ± 3 mmHg in IL-6 + L). CONCLUSION: These data indicate that IL-6 stimulates AT1-AA and that activation of the AT1R mediates IL-6 induced hypertension during pregnancy.

Acute effects of interleukin-6 infusion on apo-B-containing lipoprotein subclasses in humans

IL-6 is believed to mediate the elevation in plasma TG and VLDL lipids in patients with sepsis. Previous studies of lipoprotein density fractions do not reveal the extent to which cytokines change the immunochemically distinct TG-rich (LpB:C, LpB:C:E, LpAII:B:C:D:E) and cholesterol-rich (LpB, LpB:E) apoB-containing subclasses present in VLDL. Therefore, we have directly measured these subclasses following their isolation by sequential immunoprecipitation in seven healthy male subjects during a 3-h infusion with recombinant human (rh) IL-6. Though plasma TG and apoB-containing particle number were unchanged by IL-6, the distribution of TG-rich subclasses was significantly altered. Compared to baseline values, LpB:E + LpB:C:E increased significantly at 0.5 h (p < 0.02) and were higher than saline-infused controls at 0.5 and 1 h (p < 0.05). At 0.5 h LpAII:B:C:D:E reciprocally declined from baseline (p < 0.01). While the pattern of change for total apoB showed an overall decline (p < 0.05), these changes in LpB:E + LpB:C:E and LpAII:B:C:D:E in IL-6 subjects differed from controls (p < 0.05; p < 0.01, respectively). These findings indicate that physiologic concentrations of IL-6 rapidly and selectively regulate the transport of apoB particles that contain apoE. Since apoE has immunomodulatory and host defense functions, these changes may be a previously unrecognized early step in the innate immune response.

Should High-Dose Interleukin-2 Still be the Preferred Treatment for Patients with Metastatic Renal Cell Cancer?

Interleukin-2 (IL-2) was the preferred treatment for medically fit patients with advanced kidney cancer, but recently, several targeted therapies have been approved for metastatic renal cell carcinoma. We wished to determine the long-term survival rate for patients with kidney cancer treated with IL-2 and whether the use of intense inpatient IL-2 has declined since the introduction of targeted therapies. Patients who received IL-2 were identified from clinical trial enrollment, pharmacy logs, and financial billing records. Survival was determined from the earliest date of IL-2 therapy. There were 79 patients hospitalized for high-dose infusional IL-2 between March 1989 and March 2009. Median age was 58 years, and 27% were older than 65 years at the time of treatment. At the time of this analysis, 72 patients had deceased. Median survival was 9.9 months, but 5-year survival was 19.4%. The average number of patients with IL-2 increased from 2.2 per year during 1989-1992 to 5.6 during 1993-2001 after FDA approval, but dropped to 2.0 during 2002-2009. High-dose IL-2 is associated with a 5-year survival rate that is higher than objective response rates, suggesting a delayed immunotherapy benefit for some patients. The use of intensive IL-2 has declined dramatically in recent years, but unless a long-term survival benefit can be shown for these new targeted products, we feel that inpatient IL-2 remains the preferred initial treatment.

Correlation between lymphocyte counts and response to outpatient intravenous interleukin-2 preceded by famotidine in metastatic melanoma.

8585 Background: Increased numbers of peripheral blood lymphocytes have been seen in patients receiving high-dose continuous and bolus infusion Interleukin-2 (IL-2) regimens. The toxicity of high-dose IL-2 due to a “capillary leak” syndrome requires in-patient administration of such regimens. Daily intravenous doses of IL-2 of 18-21.6 MIU/m2 over 15-30 minutes have been developed to attempt to lessen toxicity of this therapy. Famotidine may increase Interleukin-2 internalization by the IL-2 receptor on lymphocytes (Tsunoda, 1992). Previously, we have shown that patients with metastatic melanoma may be treated safely with outpatient intravenous Interleukin-2 preceded by intravenous famotidine daily for 3-5 days (Quan et al, 2003; Quan et al, 2010). The current study involves 17 patients with metastatic melanoma. Methods: Thirteen patients with stage IV melanoma received IL-2 18 MIU/m2 intravenously (IV) preceded by famotidine 20 mg IV daily for 3 days for six consecutive weeks. Four patients with metastatic melanoma received IL-2 21.6 MIU/m2 IV preceded by famotidine 20 mg IV daily for four days every 3 weeks. Peripheral blood lymphocyte counts were measured on the first day of each week of IL-2 therapy for all patients. Student’s t-test was used to compare the highest lymphocyte counts in responding patients vs. non-responders. Results: Four patients experienced either a complete (2) or partial (2) response. Thirteen patients were non-responders. The median lymphocyte count achieved in the responding patients was 4750/mm3 (range: 3100-5314/mm3) compared to the median of 2400/mm3 (range: 1500-4949/mm3) in the non-responders (p = 0.008). Conclusions: Peripheral blood lymphocyte numbers are significantly higher in patients with metastatic melanoma responding to outpatient intravenous Interleukin-2 preceded by famotidine than in non-responders. Further studies using flow cytometry and lymphocyte cytoxicity assays are currently being done.

Clinical Efficacy of Chemotherapy Combined with Verapamil in Metastatic Colorectal Patients

In order to determine the clinical efficacy and adverse reactions of chemotherapy and verapamil infusion through a target artery to treat colorectal cancer patients with metastasis after failure with previous conventional treatments. Patients with metastatic colon cancer (n = 36) received an infusion of verapamil, interleukin-2, oxaliplatin (or hydroxy camptothecin or irinotecan hydrochloride), fluorouracil and calcium folinate through target artery using the Seldinger puncture technique. From the second day of infusion, the patients were treated with fluorouracil and calcium folinate via systematic intravenous injection for 2-3 days. Efficacy was evaluated after at least two treatment courses. The objective response including complete or partial response was 58.3% in the 36 patients; clinical benefit rate, evaluated by Karnofsky Performance Status score was 91.7%; by weight was 83.3%; by the amount of painkiller consumed was 80.6%. No patient experienced side effects associated with heart function. Post-treatment, the P-R period, Q-T period, QRS, and heart rate were not significantly different than before treatment. Liver function was significantly improved. Side effects of chemotherapy were minor in comparison to those observed with intravenous chemotherapy. Infusion of verapamil and chemotherapy directly into pelvic tumor tissue can increase treatment efficacy and has been shown to be a relatively safe technique.

IL-6, but not TNF-α, increases plasma YKL-40 in human subjects

Plasma levels of YKL-40 are elevated in patients with systemic infection, inflammatory disorders and cancer. Both monocytes/macrophages, neutrophils, and cancer cells have the capacity to produce YKL-40, but the regulation during the inflammatory response is unknown. To study the possible role of interleukin-6 (IL-6) and tumor necrosis factor (TNF)-α in the regulation of YKL-40 plasma levels, we included healthy men, who received either recombinant human (rh)IL-6 ( n = 6), rhTNF-α ( n = 8) or vehicle ( n = 7) for 3 h. The plasma levels of IL-6 and TNF-α reached ∼150 and ∼18 pg/ml, respectively, during the infusions. Following the IL-6 infusion, the plasma level of YKL-40 increased from ∼30 to ∼57 ng/ml ( p < 0.05) at 24 h, and returned to normal values after 48 h. The plasma level of YKL-40 did not change during TNF-α infusion or infusion of vehicle. These data demonstrate that IL-6, but not TNF-α, has a key-role in the regulation of plasma YKL-40 levels during inflammation.

Renal vasoconstrictor as well as natriuretic responses to human recombinant interleukin‐6 administration in anesthetized mice

Recent studies have implicated a role for interleukin-6 (IL-6) in the pathophysiology of hypertension. To examine its direct effects on renal function, we examined the renal responses to i.v. infusion of human recombinant IL-6 in anesthetized mice (C57BL/6). Arterial pressure (AP) was recorded from a carotid arterial cannula and urine was collected from a cannula inserted into the bladder. Renal blood flow (RBF) and glomerular filtration rate (GFR) were determined by PAH and inulin clearances. Following the consecutive two 30 min control clearance collections, IL-6 was infused at incremental doses (0.015, 0.03, and 0.06 ng/g/min). At each dose, a 30 min collection was performed following a 15 min stabilization period. IL-6 caused small but significant decreases in AP (96±4 to 86±3 mmHg), RBF (6.8±0.5 to 6.2±0.6 mL/min/g) and GFR (0.97±0.08 to 0.85±0.10 mL/min/g) at the highest dose but not at the lowest dose. However, there were significant increases in absolute (0.4±0.03 to 1.2±0.4 μmol/min/g) and fractional excretion of sodium (0.3±0.04 to 1.1±0.3%) at the lowest dose which were attenuated at higher doses of IL-6. These responses to IL-6 were absent in mice pretreated with an IL-6 blocker, Tocilizumab (8 mg/kg, ip; 24 and 3 hrs before IL-6 infusion). These data demonstrate that natriuretic action of IL-6 is usually compromised by its hypotensive and vasoconstrictor actions in the kidney.

Hepcidin and Anemia of the Critically Ill Patient

A NEMIA occurs frequently in critically ill patients, with 60–66% of them having anemia when admitted to the intensive care unit (ICU), and is associated with worse outcomes (such as increased length of stay and increased mortality). Anemia is only partially corrected during ICU stay because recent recommendations have led to a decrease in transfusion triggers. Today the prevalence of anemia in patients being discharged from the ICU is very high, being found in at least 75% of the patients upon final hemoglobin measurement. This common, and severe anemia at ICU discharge may also be prolonged after the ICU stay. The median time to recovery of anemia is 11 weeks. One observational study reports that more than half of such patients are still anemic at 6 months. Although the impact of anemia on rehabilitation after ICU discharge or quality of life has not been fully evaluated, it is well accepted that anemia is associated with worse outcomes for postoperative rehabilitation and for patients with chronic diseases such as cancer and thus should retain our interest at the bedside and in the research unit. Because blood transfusion is not an option for complete correction of this anemia, one may advocate the use of other treatments, such as erythropoiesis-stimulating agents (ESA) or iron. ESA efficacy has been studied in critically ill patients and has not proven to be indicated, at least according to the design of the studies. Iron is needed for erythropoiesis and thus may be indicated for the treatment of this anemia, but iron is also a toxic compound with the ability to induce oxidative stress or promote bacterial growth. A better understanding of iron metabolism regulation may help to define the place of iron in these indications. The recent discovery of hepcidin (i.e., the master regulator of iron metabolism) has shed new light on the regulation of iron homeostasis and has increased understanding of the physiopathology of anemia in complex clinical situations where several regulatory circuits interfere with iron metabolism, such as anemia of inflammation and anemia of critically ill patients. This article reviews the link between iron metabolism and anemia in critically ill patients and discusses therapeutic perspectives in this area.

Interleukin-6: a growth factor stimulating collagen synthesis in human tendon

Human connective tissue, e.g., tendon, responds dynamically to physical activity, with collagen synthesis being increased after both acute and prolonged exercise or training. Markers of collagen synthesis and degradation as well as concentration of several potential growth factors have been shown to increase markedly in the peritendinous tissue around the human Achilles tendon following exercise. Of these potential growth factors interleukin-6 (IL-6) showed the largest fold increase, suggesting that IL-6 may be involved in transforming mechanical loading into collagen synthesis in human tendon tissue. In the present study the tissue levels of type I collagen turnover markers [procollagen type I NH(2)-terminal propeptide (PINP) and C-OOH terminal telopeptide of type I collagen (ICTP)] were measured by the use of microdialysis in peritendinous tissue of the Achilles tendon in 14 male volunteers, who had recombinant human IL-6 (rhIL-6) infused into the peritendinous tissue of the Achilles' tendon in one leg, with the other leg serving as control. Subjects were randomly assigned to either a resting group or an exercise group performing a 1-h treadmill run (12 km/h, 2% uphill) before infusion. In addition to IL-6, serum concentrations of collagen turnover markers PINP, ICTP, and COOH-terminal telopeptide of type I collagen (ICTX) were measured. The peritendinous concentration of PINP rose markedly in response to rhIL-6 infusion in both the exercise and the rest group, demonstrating that infusion of IL-6 significantly stimulates collagen synthesis in the peritendinous tissue in humans. Exercise alone did not result in an increased collagen synthesis. This indicates that IL-6 is involved in the collagen synthesis and supports the hypothesis that IL-6 is an important growth factor of the connective tissue in healthy human tendons.