Exploratory assessment of the effect of systemic administration of soluble glycoprotein 130 on cognitive performance and chemokine levels in a mouse model of experimental traumatic brain injury.

Uncontrolled neuroinflammation mediates traumatic brain injury (TBI) pathology and impairs recovery. Interleukin-6 (IL-6), a pleiotropic inflammatory regulator, is associated with poor clinical TBI outcomes. IL-6 operates via classical-signaling through membrane-bound IL-6 receptor (IL-6R) and trans-signaling through soluble IL-6 receptor (s)IL-6R. IL-6 trans-signaling specifically contributes to neuropathology, making it a potential precision therapeutic TBI target. Soluble glycoprotein 130 (sgp130) prevents IL-6 trans-signaling, sparing classical signaling, thus is a possible treatment. Mice received either controlled cortical impact (CCI) (6.0 ± 0.2 m/s; 2 mm; 50-60ms) or sham procedures. Vehicle (VEH) or sgp130-Fc was subcutaneously administered to sham (VEH or 1 µg) and CCI (VEH, 0.25 µg or 1 µg) mice on days 1, 4, 7, 10 and 13 post-surgery to assess effects on cognition [Morris Water Maze (MWM)] and ipsilateral hemisphere IL-6 related biomarkers (day 21 post-surgery). CCI + sgp130-Fc groups (0.25 µg and 1 µg) were combined for analysis given similar behavior/biomarker outcomes. CCI + VEH mice had longer latencies and path lengths to the platform and increased peripheral zone time versus Sham + VEH and Sham + sgp130-Fc mice, suggesting injury-induced impairments in learning and anxiety. CCI + sgp130-Fc mice had shorter platform latencies and path lengths and had decreased peripheral zone time, indicating a therapeutic benefit of sgp130-Fc after injury on learning and anxiety. Interestingly, Sham + sgp130-Fc mice had shorter platform latencies, path lengths and peripheral zone times than Sham + VEH mice, suggesting a beneficial effect of sgp130-Fc, independent of injury. CCI + VEH mice had increased brain IL-6 and decreased sgp130 levels versus Sham + VEH and Sham + sgp130-Fc mice. There was no treatment effect on IL-6, sIL6-R or sgp130 in Sham + VEH versus Sham + sgp130-Fc mice. There was also no treatment effect on IL-6 in CCI + VEH versus CCI + sgp130-Fc mice. However, CCI + sgp130-Fc mice had increased sIL-6R and sgp130 versus CCI + VEH mice, demonstrating sgp130-Fc treatment effects on brain biomarkers. Inflammatory chemokines (MIP-1ß, IP-10, MIG) were increased in CCI + VEH mice versus Sham + VEH and Sham + sgp130-Fc mice. However, CCI + sgp130-Fc mice had decreased chemokine levels versus CCI + VEH mice. IL-6 positively correlated, while sgp130 negatively correlated, with chemokine levels. Overall, we found that systemic sgp130-Fc treatment after CCI improved learning, decreased anxiety and reduced CCI-induced brain chemokines. Future studies will explore sex-specific dosing and treatment mechanisms for sgp130-Fc therapy.

Assessment of serum inflammatory parameters in RRMS and SPMS patients.

OBJECTIVES: Multiple sclerosis (MS) is a chronic autoimmune inflammatory disease. Patients with relapsing-remitting MS (RRMS) and secondary progressive MS (SPMS) differ in their responses to treatment; therefore, the correct diagnosis of the particular type of MS is crucial, and biomarkers that can differentiate between the forms of MS need to be identified. The aim of this study was to compare the levels of inflammatory parameters in serum samples from patients with RRMS and SPMS. METHODS: The study group consisted of 60 patients with diagnosed MS. The patients were divided into RRMS and SPMS groups. In the RRMS patients, the usage of disease-modifying treatment was included in our analysis. The serum levels of inflammatory parameters were evaluated. RESULTS: The serum levels of BAFF, gp130 and osteopontin were significantly higher in SPMS patients than in RRMS patients. The serum levels of BAFF correlated with age in both RRMS and SPMS patients. The serum levels of MMP-2 were significantly higher in RRMS patients than in SPMS patients and correlated with the number of past relapses. The serum levels of IL-32 were significantly higher in RRMS treatment-naïve patients than in RRMS patients treated with disease-modifying therapy. DISCUSSION: Significant differences were found in BAFF, gp130, MMP-2 and osteopontin levels between RRMS and SPMS patients. Serum IL-32 levels were statistically lower in RRMS patients treated with disease-modifying therapy than in treatment-naïve patients.

Circulating interleukin 6 and soluble forms of its receptors in relation to resting energy expenditure in women with anorexia nervosa.

CONTEXT: Anorexia nervosa (AN) is an eating disorder, resulting in sustained low weight and marked decrease in fat mass. Interleukin 6 (IL-6) may play a role in appetite, energy expenditure and body weight control. IL-6 acts through binding with membrane receptor (IL-6R) and activates glycoprotein 130 (gp130) signalling. Both IL-6R and gp130 are present in the blood in the soluble forms (sIL-6R and sgp130 respectively). sIL-6R sensitizes cells towards IL-6, whereas sgp130 inhibits gp130 signalling. OBJECTIVE: To estimate circulating IL-6/sIL-6R/sgp130 system and its relationships with body weight and resting energy expenditure (REE) in AN women. PATIENTS: We examined 19 women with AN and 27 healthy normal-weight female controls. MEASUREMENTS: Indirect calorimetry and the measurement of serum IL-6, sIL-6R and sgp130 concentrations were performed in all the subjects. RESULTS: REE was decreased in AN women (P < 0·001). Serum IL-6 was higher in AN women in comparison with control group (P = 0·005). Serum sIL-6R was lower (P = 0·009) and serum sgp130 was higher (P = 0·004) in AN women in comparison with controls. IL-6 and sIL-6R were related to REE in the entire study population (r = -0·54, P < 0·001 and r = 0·48, P = 0·001 respectively) and in AN group (r = -0·54, P = 0·024 and r = 0·60, P = 0·011 respectively). CONCLUSIONS: Increased IL-6 in AN seems to be compensated by the changes in sIL-6R and sgp130, which are directed towards inhibition of IL-6 action. The balance between these factors might play a role in the regulation of energy expenditure in AN.

Newer biological agents in the treatment of rheumatoid arthritis: do the benefits outweigh the risks?

Recently, three new biological agents, rituximab, abatacept and tocilizumab, have become available for the treatment of rheumatoid arthritis (RA) in patients with active disease, who have not responded to at least one disease-modifying antirheumatic drug (DMARD). Rituximab is an anti-CD20 monoclonal antibody, abatacept modulates T-cell activation and tocilizumab is an interleukin-6 receptor antagonist. Clinical studies with these agents have demonstrated that they are effective in RA patients with moderate to active disease, who have not responded to treatment with at least one DMARD and/or tumour necrosis factor (TNF) inhibitor. Thus far, there is no convincing evidence to show that one of these three new drugs has a superior efficacy over the others or that they have other benefits compared with the TNF inhibitors. The use of rituximab, instead of another TNF inhibitor, might be an option in patients who have not responded to TNF blockade. Abatacept could also be considered, but this has not yet been formally tested. A practical advantage of tocilizumab is that it may be administered as a first-line biological agent. Adverse events, including (usually mild) infusion reactions, are common. There is a small increased risk of serious infections that appears to be similar to that with TNF inhibitors, although each drug may have its own particular risk profile. Thus far, there is no convincing evidence that the new biological agents are associated with an increased risk of malignancies. However, the number of patient-years studied is still rather limited and, hence, continuous postmarketing surveillance is necessary. Adequate studies directly comparing new biological agents with each other and with other biological agents, such as TNF inhibitors, are not available. Hence, no firm conclusions regarding the benefit-risk profile of these agents versus each other can be reached. However, the benefit for a given new biological agent currently appears to outweigh the risk for an individual RA patient with active disease, despite earlier drug treatment.