Cytokine regulation of skeletal muscle fatty acid metabolism: effect of interleukin-6 and tumor necrosis factor-α

IL-6 and TNF-α have been associated with insulin resistance and type 2 diabetes. Furthermore, abnormalities in muscle fatty acid (FA) metabolism are strongly associated with the development of insulin resistance. However, few studies have directly examined the effects of either IL-6 or TNF-α on skeletal muscle FA metabolism. Here, we used a pulse-chase technique to determine the effect of IL-6 (50-5,000 pg/ml) and TNF-α (50-5,000 pg/ml) on FA metabolism in isolated rat soleus muscle. IL-6 (5,000 pg/ml) increased exogenous and endogenous FA oxidation by ≃50% (P < 0.05) but had no effect on FA uptake or incorporation of FA into endogenous lipid pools. In contrast, TNF-α had no effect on FA oxidation but increased FA incorporation into diacylglycerol (DAG) by 45% (P < 0.05). When both IL-6 (5,000 pg/ml) and insulin (10 mU/ml) were present, IL-6 attenuated insulin's suppressive effect on FA oxidation, increasing exogenous FA oxidation (+37%, P < 0.05). Furthermore, in the presence of insulin, IL-6 reduced the esterification of FA to triacylglycerol by 22% (P < 0.05). When added in combination with IL-6 or leptin (10 μg/ml), the TNF-α-induced increase in DAG synthesis was inhibited. In conclusion, the results demonstrate that IL-6 plays an important role in regulating fat metabolism in muscle, increasing rates of FA oxidation, and attenuating insulin's lipogenic effects. In contrast, TNF-α had no effect on FA oxidation but increased FA incorporation into DAG, which may be involved in the development of TNF-α-induced insulin resistance in skeletal muscle.

Interleukin-6 and tumor necrosis factor-α are not increased in patients with type 2 diabetes: Evidence that plasma interleukin-6 is related to fat mass and not insulin responsiveness

Aims/hypothesis. Our aim was to examine the possible direct relationship of interleukin-6 and TNFα with insulin sensitivity in humans. Methods. We carried out two series of euglycaemic-hyperinsulinaemic clamp experiments. In the first (CLAMP1), skeletal muscle mRNA expression and plasma concentrations of IL-6 and TNFα were examined in patients with Type 2 diabetes (n=6), subjects matched for age (n=6), and young healthy (n=11) control subjects during a 120-min supra-physiological hyperinsulinaemic (40 mU·m -2·min-1) euglycaemic clamp. In the second series of experiments (CLAMP2), patients with Type 2 diabetes (n=6) and subjects matched for age (n=7) were studied during a 240-min high-physiological hyperinsulinaemic (7 mU·m-2·min-1) euglycaemic clamp, during which arterial and venous (femoral and subclavian) blood samples were measured for IL-6 and TNFα flux. Results. In both experiments the glucose infusion rate in the patients was markedly lower than that in the other groups. In CLAMP1, basal skeletal muscle IL-6 and TNFα mRNA were the same in all groups. They were not affected by insulin and they were not related to the glucose infusion rate. In CLAMP2, neither cytokine was released from the arm or leg during insulin stimulation in either group. In both experiments plasma concentrations of these cytokines were similar in the patients and in the control subjects, although in CLAMP1 the young healthy control group had lower (p<0.05) plasma IL-6 concentrations. Using data from all subjects, a strong positive correlation (r=0.85; p<0.00001) was observed between basal plasma IL-6 and BMI. Conversely, a negative relationship (r=-0.345; p<0.05) was found between basal plasma TNFα and BMI, although this was not significant when corrected for BMI. When corrected for BMI, no relationship was observed between either basal plasma IL-6 or TNFα and GIR. Conclusions/interpretation. These data show that the increased circulating IL-6 concentrations seen in patients with Type 2 diabetes are strongly related to fat mass and not insulin responsiveness, and suggest that neither IL-6 nor TNFα are indicative of insulin resistance.

Interleukin-10 inhibits bone resorption: a potential therapeutic strategy in periodontitis and other bone loss diseases

Periodontitis and other bone loss diseases, decreasing bone volume and strength, have a significant impact on millions of people with the risk of tooth loss and bone fracture. The integrity and strength of bone are maintained through the balance between bone resorption and bone formation by osteoclasts and osteoblasts, respectively, so the loss of bone results from the disruption of such balance due to increased resorption or/and decreased formation of bone. The goal of therapies for diseases of bone loss is to reduce bone loss, improve bone formation, and then keep healthy bone density. Current therapies have mostly relied on long-term medication, exercise, anti-inflammatory therapies, and changing of the life style. However there are some limitations for some patients in the effective treatments for bone loss diseases because of the complexity of bone loss. Interleukin-10 (IL-10) is a potent anti-inflammatory cytokine, and recent studies have indicated that IL-10 can contribute to the maintenance of bone mass through inhibition of osteoclastic bone resorption and regulation of osteoblastic bone formation. This paper will provide a brief overview of the role of IL-10 in bone loss diseases and discuss the possibility of IL-10 adoption in therapy of bone loss diseases therapy.

Identification of a gene for an ancient cytokine, interleukin 15-like, in mammals; interleukins 2 and 15 co-evolved with this third family member, all sharing binding motifs for IL-15Rα

Interleukins 2 and 15 (IL-2 and IL-15) are highly differentiated but related cytokines with overlapping, yet also distinct functions, and established benefits for medical drug use. The present study identified a gene for an ancient third IL-2/15 family member in reptiles and mammals, interleukin 15-like (IL-15L), which hitherto was only reported in fish. IL-15L genes with intact open reading frames (ORFs) and evidence of transcription, and a recent past of purifying selection, were found for cattle, horse, sheep, pig and rabbit. In human and mouse the IL-15L ORF is incapacitated. Although deduced IL-15L proteins share only ~21 % overall amino acid identity with IL-15, they share many of the IL-15 residues important for binding to receptor chain IL-15Rα, and recombinant bovine IL-15L was shown to interact with IL-15Rα indeed. Comparison of sequence motifs indicates that capacity for binding IL-15Rα is an ancestral characteristic of the IL-2/15/15L family, in accordance with a recent study which showed that in fish both IL-2 and IL-15 can bind IL-15Rα. Evidence reveals that the species lineage leading to mammals started out with three similar cytokines IL-2, IL-15 and IL-15L, and that later in evolution (1) IL-2 and IL-2Rα receptor chain acquired a new and specific binding mode and (2) IL-15L was lost in several but not all groups of mammals. The present study forms an important step forward in understanding this potent family of cytokines, and may help to improve future strategies for their application in veterinarian and human medicine.

Identification and characterisation of a novel Interleukin-4 receptor antagonist for allergy treatment

 The main focus of the PhD studies was the identification and characterization of a peptide antagonist which inhibited and/or down-regulated the binding of Interleukin-4 receptor to its cytokines IL-4 and IL-13 for allergy treatment. In addition, dietary components were tested for their ability to reduce inflammatory pathways of allergy, including fatty acids, resolvins and coenzyme Q10. Lastly, the Deakin AIRwatch project was undertaken which included the collection of ryegrass pollen data from 2012-2014 and its correlation with meteorological variables in regional Victoria.

Osteoclast formation elicited by interleukin-33 stimulation is dependent upon the type of osteoclast progenitor

Osteoclasts are bone resorbing multinucleated cells (MNCs) derived from macrophage progenitors. IL-33 has been reported to drive osteoclastogenesis independently of receptor activator of NFκB ligand (RANKL) but this remains controversial as later studies did not confirm this. We found IL-33 clearly elicited functional dentine-resorbing osteoclast formation from human adult monocytes. However, monocytes from only 3 of 12 donors responded this way, while all responded to RANKL. Human cord blood-derived progenitors and murine bone marrow macrophages lacked an osteoclastogenic response to IL-33. In RAW264.7 cells, IL-33 elicited NFκB and p38 responses but not NFATc1 signals (suggesting poor osteoclastogenic responses) and formed only mononuclear tartrate-resistant acid phosphatase positive (TRAP(+)) cells. Since TGFβ boosts osteoclastogenesis in RAW264.7 cells we employed an IL-33/TGFβ co-treatment, which resulted in small numbers of MNCs expressing key osteoclast markers TRAP and calcitonin receptors. Thus, IL-33 possesses weak osteoclastogenic activity suggesting pathological significance and, perhaps, explaining previous conflicting reports.

Effects of resistance or aerobic exercise training on interleukin-6, C-reactive protein, and body composition

PURPOSE: To determine the effects of 10 wk of resistance or aerobic exercise training on interleukin-6 (IL-6) and C-reactive protein (CRP). Further, to determine pretraining and posttraining associations between alterations of IL-6 and CRP and alterations of total body fat mass (TB-FM), intra-abdominal fat mass (IA-FM), and total body lean mass (TB-LM). METHODS: A sample of 102 sedentary subjects were assigned to a resistance group (n = 35), an aerobic group (n = 41), or a control group (n = 26). Before and after intervention, subjects were involved in dual-energy x-ray absorptiometry, muscular strength and aerobic fitness, measurements and further provided a resting fasted venous blood sample for measures of IL-6, CRP, cholesterol profile, triglycerides, glucose, insulin, and glycosylated hemoglobin. The resistance and the aerobic groups completed a respective 10-wk supervised and periodized training program, whereas the control group maintained sedentary lifestyle and dietary patterns. RESULTS: Both exercise training programs did not reduce IL-6; however, the resistance and the aerobic groups reduced CRP by 32.8% (P < 0.05) and 16.1% (P = 0.06), respectively. At baseline, CRP was positively correlated with IL-6 (r = 0.35), (TB-FM) (r = 0.36), and IA-FM (r = 0.31) and was inversely correlated with aerobic fitness measures (all r values > or = -0.24). Compared with the resistance and the control groups, the aerobic group exhibited significant (P < 0.05) improvements in all aerobic fitness measures and significant reductions in IA-FM (7.4%) and body mass (1.1%). Compared with the aerobic and the control groups, the resistance group significantly (P < 0.05) improved TB-FM (3.7%) and upper (46.3%) and lower (56.6%) body strength. CONCLUSION: Despite no alteration in baseline IL-6 and significantly smaller reductions in measures of adipose tissue as compared with the aerobic training group, only resistance exercise training resulted in significant attenuation of CRP concentration.

Investigating interleukin-2 receptor family signaling in zebrafish

The zebrafish possesses all of the interleukin 2 receptor family except interleukin 2 receptor alpha and removal of the common signalling component interleukin 2 receptor gamma causes a human like severe combined immunodeficiency.