Targeting gp130 to prevent inflammation and promote insulin action.

Obesity and type 2 diabetes are now the most prevalent metabolic diseases in the Western world and the development of new strategies to treat these metabolic diseases is most warranted. Obesity results in a state of chronic low-grade inflammation in metabolically active tissues such as the liver, adipose tissue, brain and skeletal muscle. Work in our laboratory has focussed on the role of the cytokine interleukin-6 (IL)-6 and other IL-6-like cytokines that signal through the gp130 receptor complex. We have focussed on the role of blocking IL-6 trans-signalling to prevent inflammation on the one hand, and activating membrane-bound signalling to promote insulin sensitivity on the other hand. Since the cloning of the IL-6 gene nearly 30 years ago, a pattern has emerged associating IL-6 with a number of diseases associated with inflammation including rheumatoid arthritis (RA), Crohn's disease and several cancers. Accordingly, tocilizumab, an IL-6 receptor-inhibiting monoclonal antibody, is now useful for the treatment of RA. However, this may not be the most optimal strategy to block inflammation associated with IL-6 and may result in unwanted side effects that, paradoxically, could actually promote metabolic disease.

Effect of blood handling on extracellular Hsp72 concentration after high-intensity exercise in humans.

Heat shock protein 72 (Hsp72) has been detected in the peripheral circulation of humans. Because intracellular Hsp72 binds to aggregated proteins, we hypothesized that postexercise plasma-derived Hsp72 concentrations would be greater than serum-derived Hsp72 because of binding of Hsp72 to aggregated clotting proteins in serum. Postexercise serum, heparin, and ethylenediaminetetraacetic acid (EDTA) samples were collected from 9 recreationally active males and were analyzed for Hsp72 by enzyme-linked immunosorbent assay. In line with our hypothesis, EDTA-treated blood was significantly higher in Hsp72 concentration than all other treatments (P < or = 0.001), whilst heparin plasma (LH) was significantly higher than serum derived on ice (SI) and at room temperature (SR) (P < 0.05; EDTA: 6.46 +/- 0.76, LH: 2.73 +/- 2.26, SI: 0.13 +/- 0.24, SR: 0.20 +/- 0.32 ng/mL). Because previous research has tended to report serum data at the lowest point of the detectable range of the assay, it is recommended that EDTA specimen tubes be used in future investigations.

Leukocyte heat shock protein expression before and after intensified training.

The purpose of the current research was to test the hypothesis that exercise induced leukocyte heat shock protein (HSP) expression is increased during periods of intensified exercise training. Seven male endurance cyclists carried out tests of maximal oxygen consumption and endurance capacity. These standard exercise tests were carried out prior to and following 6 days of prescribed intensified training. Sampled leukocytes were examined for Hsp27 and Hsp70 expression using a Fluorescence Activated Cell Scanner (EPICS XL, Coulter). During a period of overreaching, as signified by a drop in time to fatigue following the intensified training period (p = 0.02), the number of extracellular Hsp27 positive granulocytes increased in response to the VO(2)max test. Acute, intracellular HSP responses were observed in both baseline and overreached conditions. The present study showed that a period of intensified training caused adaptations in the acute heat shock protein exercise response, reflected by a greater increase of cell surface HSP positive leukocytes following heavy training.

The effect of exercise training on the kinetics of the antibody response to influenza vaccination.

The significance of in vitro changes in immune function accompanying exercise training is unclear. To determine the effect of exercise on the response of the intact immune system to a challenge in vivo, we measured the speed and overall immunoglobulin G (IgG) response to influenza vaccination in humans engaged in different intensities of activity. Male participants (n = 21) were split into heavy and light training groups. Venous blood samples were collected 0, 2, 4, 7, 10 and 14 days after vaccination with trivalent influenza vaccine, and also 12 months after initial vaccination. Serum IgG was determined by enzyme-linked immunosorbant assay. There was a significant difference in baseline IgG between groups, but no difference in IgG concentration 14 days after vaccination. The IgG concentration remained elevated 12 months post-vaccination in the heavy training group. The results suggest a positive relationship between habitual physical activity and baseline antibody concentrations, which, in turn, affects the relative magnitude (fold or percentage increase) of the antibody response to vaccination. The training loads of the participants in this study had no effect on overall IgG measured 14 days after vaccination.

The effects of radiotherapy on immunity in patients with cured localized carcinoma of the cervix uteri.

The effects of radiotherapy on immune status in patients with localized carcinoma of the cervix have been assessed serially up to 5 years remission by a wide range of methods. Neutrophil function and serum immunoglobulins were essentially normal throughout. Peripheral blood neutrophil and lymphocyte counts and the proportions of T and B-cells fell with treatment but were all normal at 5 years, with the exception of B-cell proportions which remained significantly low. Marked deterioration was seen in in vivo cellular immune responses and this persisted even at 5 years remission. Reduced in vitro immunoreactivity is not therefore a reliable marker of disease recurrence and persisting defects in cellular immunity after radiotherapy do not seem to adversely affect the host tumor response. However, in three of the six patients who subsequently relapsed after therapy, subnormal PHA lymphocyte transformation responses were observed at presentation; all patients achieving sustained remission had normal pretreatment responses.

Immunity in Hodgkin's disease: status after 5 years' remission.

Immunological indices have been reassessed in 27 patients in remission from Hodgkin's disease for 5 years after treatment and the findings correlated with initial treatment and splenectomy status. Neutrophil counts were lower and lymphocyte and monocyte counts higher at 5 years' remission than at presentation; the increases in lymphocyte count were mainly a feature of the splenectomized patients. Neutrophil function (nitro-blue tetrazolium) was unchanged in remission but cellular immunity (leucocyte migration inhibition and lymphocyte transformation) was depressed at 5 years and progressive falls in serum immunoglobulins were noted. Low values of IgG and IgM were particularly found in patients who had splenectomy and chemotherapy; there was however no excess of infections in this small group.

Liver DNA bound in vivo with aflatoxin B1 as a measure of hepatocarcinoma initiation in rainbow trout.

The in vivo binding of aflatoxin B1 (AFB1) to liver DNA was measured in rainbow trout subjected to various regimens and in coho salmon to determine if binding would correlate with tumor incidence and initiation of hepatocellular carcinoma. Establishment of time-course binding parameters showed no significant difference between 4, 12, 24, or 48 hours. Doses of 5, 25, 100, and 300 micrograms AFB1/kg body weight produced an almost linear increase in binding with increasing dose. Compared to that of controls, AFB1-DNA binding was twofold lower in beta-naphthoflavone-treated trout and twentyfold lower in coho salmon. These two comparisons reflected a decrease in the effective activation and binding of AFB1, correlated with tumor incidence, and are believed to correlate with a decrease in the initiation of hepatocellular carcinoma. AFB1 binding was not significantly altered by dietary protein or cyclopropenoid fatty acids, which are thought to increase hepatocellular carcinoma incidence through promotional effects. The data were consistent with the view that in vivo binding of AFB1 to liver DNA is a measure of cancer inititation by AFB1 and correlated with the incidence of hepatocellular carcinoma in salmonid fish.