Interleukin-6: From identification of the cytokine to development of targeted treatments

Interleukin-6 (IL-6) was identified based on extensive research conducted simultaneously on a variety of topics ranging from hepatocyte production of acute-phase proteins to plasmacytoma growth. IL-6 is a cytokine produced by a broad array of cell types and can exert its effects on virtually all cells. IL-6 can induce cell signaling not only via the classic pathway involving the transmembrane receptor IL-6Rα (restricted cellular expression) associated with gp130 (ubiquitous and responsible for signal transmission), but also via the soluble receptor IL-6Rα, which binds to IL-6 and induces a signal mediated by the ubiquitous gp130 molecule (transsignaling). IL-6 is deregulated in many inflammatory and autoimmune diseases, including rheumatoid arthritis (RA). By virtue of its multiple effects, IL-6 is involved in the various phases of RA development, including the acute phase, immuno-inflammatory phase, and destructive phase. IL-6 has an impact on the many pathogenic factors identified in RA and, consequently, holds promise for targeted treatments. However, anti-IL-6 monoclonal antibodies evaluated as IL-6 antagonists, instead, increased the half-life of the cytokine. In contrast, monoclonal antibody (tocilizumab) to transmembrane and soluble IL-6Rα has been found effective in patients with RA. Tocilizumab is now indicated for the treatment of adults with RA who have failed at least one synthetic disease-modifying antirheumatic drug or TNFα antagonist.     

Benign fibrous histiocytoma of bone in a paediatric population: a report of 6 cases

Case records and radiological investigations of six children with benign fibrous histiocytoma were studied retrospectively. BFH occurred in the femur (n?=?2), tibia (n?=?2) and fibula (n?=?2). Clinically, patients reported pain from the lesion lasting several months (mean 6?months). The pain was not associated with pathological fracture in any patient. On X-rays, the lesions appeared as lytic and sharply demarcated with a sclerotic rim and fine trabeculations. The reported cases were located in the metaphysis and the diaphysis of the long bones. The tumour was restricted to bone, without periosteal or soft tissue reaction. Treatment consisted of careful intralesional curettage of the lesion; the defect was thereafter filled with bone bank graft or injectable phosphocalcic cement. The length of follow-up ranged from 24?months to 4.75?years (mean 35.2?months). One case presented with recurrence of the disease and required successful repeat intralesional curettage. Benign fibrous histiocytoma is probably underestimated among patients less than 20?years of age. This diagnosis should be considered in any child or teenager who presents with a non-ossifying fibroma accompanied by unexplainable pain or a rapid growing. Surgery restricted to the osteolytic lesion seems sufficient to achieve bone healing.     

A high prevalence of sleep disordered breathing in men with mild symptomatic chronic heart failure due to left ventricular systolic dysfunction

BACKGROUND: Sleep disordered breathing (SDB) is common in severe chronic heart failure (CHF) and is associated with increased morbidity and mortality. The prevalence of SDB in mild symptomatic CHF is unknown. AIM: The aim of this study was to determine the prevalence and characteristics of SDB in male patients with NYHA class II symptoms of CHF. METHODS AND RESULTS: 55 male patients with mild symptomatic CHF underwent assessment of quality of life, echocardiography, cardiopulmonary exercise, chemoreflex testing and polysomnography. 53% of the patients had SDB. 38% had central sleep apnoea (CSA) and 15% had obstructive sleep apnoea. SDB patients had steeper VE/VCO(2) slope [median (inter-quartile range) 31.1 (28-37) vs. 28.1 (27-30) respectively; p=0.04], enhanced chemoreflexes to carbon dioxide during wakefulness [mean+/-sd: 2.4+/-1.6 vs. 1.5+/-0.7 %VE Max/mmHg CO(2) respectively; p=0.03], and significantly higher levels of brain natriuretic peptide and endothelin-1 compared to patients without SDB. No differences in left ventricular ejection fraction, percent predicted peak oxygen uptake, or symptoms of SDB were observed. CONCLUSIONS: A high prevalence of SDB was found in men with mild symptomatic CHF. Patients with SDB could not be differentiated by symptoms or by routine cardiac assessment making clinical diagnosis of SDB in CHF difficult.     

Recruiting new neurons from the subventricular zone to the rat postnatal cortex: an organotypic slice culture model

The neurogenic subventricular zone (SVZ) of the lateral ventricle is a potential source for neuronal replacement in the postnatal or adult neocortex after injury. Here we present a novel model system to directly explore the cellular mechanisms of this process. In order to visualize directed migration from the SVZ towards the cortex, we transplanted green fluorescent protein-labeled progenitor/stem cells into the SVZ of newborn rats. At 2 days after transplantation, we generated organotypic slice cultures and applied fluorescent time-lapse imaging to explore directly the migration and integration of donor cells into the host tissue for up to 2 weeks. Our studies revealed that subventricular grafts provide a significant number of immature neurons to neocortical regions. In the cortex, immature neurons first migrate radially towards the pial surface and then differentiate into GABAergic interneurons. We conclude that our model system presents a novel and effective experimental paradigm to evaluate the recruitment of SVZ-derived neurons into the postnatal cortex, a phenomenon that may represent a potential route for cortical repair.     

ELEVATED SERUM LEVELS OF INTERLEUKIN-1 RECEPTOR ANTAGONIST IN POLYMYOSITIS/DERMATOMYOSITIS. A Biologic Marker of Disease Activity with a Possible Role in the Lack of Acute-Phase Protein Response

Objective. To determine whether the lack of acute-phase protein (APP) response in numerous patients with polymyositis/dermatomyositis (PM/DM) is related to an imbalance between cytokines and cytokine inhibitors. Methods. Levels of C-reactive protein (CRP), interleukin-1β (IL-1β), tumor necrosis factor α (TNFα), IL-6, IL-1 receptor antagonist (IL-1ra), TNF soluble receptor 55 kd (sTNFR 55 kd), and sTNFR 75 kd were tested in the serum of 15 patients with PM/DM, 14 patients with spondylarthropathies (SPA), and 12 healthy blood donors. Serum IL-1β, TNFα, IL-6, IL-1ra, sTNFR were measured by specific immunoassays. Results. Serum levels of CRP were lower in PM/DM patients than in SPA patients. Normal or slightly elevated CRP values were found in 10 of the 15 PM/DM patients, 7 of whom had active myositis. Serum IL-6 levels were significantly higher in SPA patients than in PM/DM patients, whereas serum IL-1ra and sTNFR levels were significantly higher in PM/DM than in SPA patients. IL-1ra levels were particularly elevated in patients with active myositis and decreased in response to treatment. Conclusion. These differences in cytokine levels, particularly IL-1ra, between PM/DM and SPA patients are indicative of distinct pathogenic mechanisms. High levels of IL-1ra may account for the weak APP response in some PM/DM patients. Our results suggest that measurement of IL-1ra, together with clinical examination, may provide useful information for the followup of PM/DM patients.     

Systemic sclerosis Th2 cells inhibit collagen production by dermal fibroblasts via membrane‐associated tumor necrosis factor α

Objective

In systemic sclerosis (SSc; scleroderma), T cells infiltrate organs undergoing fibrotic changes and may participate in dysregulated production of collagen by fibroblasts. The objective of this study was to functionally characterize T cells infiltrating skin lesions in early SSc and investigate their capacity to affect production of type I collagen and interstitial collagenase (matrix metalloproteinase 1 [MMP‐1]) by dermal fibroblasts.

Methods

Four‐color cytometric analysis was used to characterize subset distribution and production of interferon‐γ (IFNγ) and interleukin‐4 (IL‐4) in T cell lines generated from the skin of patients with SSc. T cell clones were generated, and their capacity to modulate collagen and MMP‐1 production by fibroblasts derived from patients with SSc and from normal individuals was assessed. Neutralizing reagents were used to identify T cell mediators involved in fibroblast modulation.

Results

The skin of individuals with early‐stage SSc contained T cells preferentially producing high levels of IL‐4. Cloned CD4+ Th2‐like cells inhibited collagen production by normal fibroblasts. Th2 cell‐dependent inhibition was, at least in part, contact‐dependent, was essentially mediated by tumor necrosis factor α (TNFα), and was dominant over the enhancement induced by profibrotic IL‐4 and transforming growth factor β cytokines. The simultaneous induction of MMP‐1 production confirmed the specificity of these observations. To be inhibitory, Th2 cells required activation by CD3 ligation. Th2 cells were less potent than were Th1 cells in inhibiting collagen production by normal fibroblasts via cell‐to‐cell interaction, and SSc fibroblasts were resistant to inhibition.

Conclusion

These findings indicate that, despite their production of IL‐4, Th2 cells reduce type I collagen synthesis by dermal fibroblasts because of the dominant effect of TNFα, and suggest that strategies based on TNFα blockade aimed at controlling fibrosis in SSc may be unwise.