Interleukin-6 (IL-6) is one of the major circulating cytokines in catabolic states. To investigate its endocrinologic and metabolic actions in vivo, we studied eight patients with metastatic renal cell cancer two times, once during infusion of saline (control) and once during a 4-h infusion of 150 micrograms recombinant human IL-6 (rhIL-6). Rates of appearance (Ra) of glucose and free fatty acids (FFA) in plasma were measured by using the isotope dilution method. Energy expenditure and substrate oxidation were determined by indirect calorimetry. rhIL-6 induced increases in plasma norepinephrine (+261 +/- 97%, P < 0.001), cortisol (+210 +/- 48%, P < 0.001), and glucagon (+70 +/- 18%, P < 0.001), in resting energy expenditure (+25 +/- 2%, P < 0.001 vs. control), and in plasma FFA concentration (+60 +/- 30%, P < 0.001), FFA Ra (+105 +/- 18%, P < 0.001), and fat oxidation (+38 +/- 16%, P < 0.001). Glucose Ra increased by 20 +/- 5% (P < 0.01) during rhIL-6 infusion with a concomitant increase in the metabolic clearance rate of glucose. In conclusion, our data demonstrate that rhIL-6 induces many of the endocrinologic and metabolic changes found in catabolic states and thus may mediate some of the metabolic effects previously ascribed to other cytokines.
SummaryThe role of IL-6 as a mediator of haemostatic changes during severe inflammation is controversial. To assess the effect of IL-6 on haemostasis we conducted a controlled cross-over study in eight patients with metastatic renal cell cancer. In all subjects coagulation and fibrinolysis were monitored during and after a 4-h infusion of either 150 μg recombinant human (rh) IL-6, or during infusion of saline (control study). Mean maximum IL-6 concentrations were 1418.0 ± 755.8 pg/ml. Compared to the control study, rhIL-6 induced activation of coagulation as reflected by a 190 ± 55% increase in the plasma levels of thrombin-antithrombin III complexes (p <0.001) and by a 24 ± 11% increase in the plasma levels of in the prothrombin activation fragment F1 + 2 (p <0.001). In contrast, fibrinolysis was not affected. We conclude that in severe inflammation IL-6 may contribute to the activation of coagulation, whereas other factors mediate changes in fibrinolysis.
Cytokines, such as tumor necrosis factor-alpha and interleukin-1 beta (IL-1 beta), alter thyroid hormone metabolism, and may be involved in the pathogenesis of the euthyroid sick syndrome. Both cytokines also induce the production of IL-6. To assess whether IL-6 itself modulates thyroid hormone metabolism, we studied the acute and chronic effects of recombinant human IL-6 (rhIL-6) on thyroid hormone concentrations in patients with renal cell cancer. In the first study protocol, plasma thyroid hormone concentrations were measured during a 4-h infusion of rhIL-6 (150 micrograms) or, on another day, during infusion of saline (control; n = 8). There were no effects of rhIL-6 infusion on T4, free T4, or thyroid hormone-binding index. However, rhIL-6 induced a significant decrease in the plasma concentrations of TSH (P < 0.001) and T3 (P < 0.001) compared with those in the control study, associated with an increase in rT3 concentrations (P < 0.001). In the second study, a dose of 150 micrograms rhIL-6 was administered sc for 42 consecutive days (n = 8). Weekly assessment of thyroid hormone and TSH concentrations showed a decrease in the T3 concentration (P < 0.001) and a transient increase in rT3 (P < 0.01) and free T4 concentrations (P < 0.01). There were no changes in T4 concentrations during chronic administration of rhIL-6. It is concluded that IL-6 induces major changes in thyroid hormone metabolism and may be another pathogenetic factor in the euthyroid sick syndrome.
In vitro as well as in vivo observations have shown that IL6 plays a key role in the pathogenesis of multiple myeloma. Therefore we started a phase I/II dose escalating study with chimeric monoclonal anti-IL6 antibodies (cMab) in multiple myeloma (MM) patients resistant to second-line chemotherapy. Here we describe the pharmacological data as well as a new method for calculating the endogenous IL6 production. During treatment with anti-IL6 cMabs, the endogenous IL6 production immediately decreased in all patients to below 3 g/d and never reached the pre-treatment value during the treatment period, except in two patients who developed an active infection, resulting in an IL6 production of 128 and 1,208 g/d, respectively. We concluded that in MM patients endogenous IL6 production is 2-30 times higher than in healthy individuals. The anti-IL6 cMab strongly suppress this endogenous IL6 production, probably by blocking a positive feed-back loop, but this cMab does not prevent infection-induced IL6 production. The chimeric anti-IL6 Mabs have a long half-life time, a low immunogenicity, and are able to block IL6-dependent processes in
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