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Introduction: Rheumatoid arthritis (RA) is a systemic autoimmune disease with IL-6 as a main mediator of systemic and localized inflammation. The most often used drug for the treatment of RA is methotrexate (MTX). Aim: To explore if there is an association between the 174G/C polymorphism in IL6 gene and response to methotrexate therapy in RA patients. Materials and Methods: Study has included 131 RA patients treated and followed at the Institute of Rheumatology in Belgrade. Clinical response to the MTX therapy was conducted following the EULAR response criteria. Each patient's DNA was isolated by salting-out method. For each patient IL6 174G/C polymorphism genotype was determined by allele specific PCR method. For statistical analyses we have used SPSS program version 17.0. Results: According to EULAR response criteria 103 (78.6 %) patients were responders 12(9.2 %) good and 91 (69.5 %) moderate response) and 28 (21.4 %) were non responders. Among all patients in 47 (35.9 %) we have detected GG genotype, in 69 (52.7 %) GC genotype and in 15 (11.5 %) CC genotype. We have observed no association between genotypes or alleles and response to MTX therapy. Conclusion: No association of -174G/C IL-6 polymorphism and therapeutic response to MTX in RA patients in Serbian population was observed.

Background Traditionally, clinical psychomotor skills are taught through videos and demonstration by faculty, which does not allow for the visualization of internal structures and anatomical landmarks that would enhance the learner skill performance. Method Sophomore and junior nursing students attending a large Midwestern institution (N = 69) participated in this mixed methods study. Students demonstrated their ability to place a nasogastric tube (NGT) after being randomly assigned to usual training (control group) or an iPad anatomy-augmented virtual simulation training module (augmented reality [AR] group). The ability of the participants to demonstrate competence in placing the NGT was assessed using a 17-item competency checklist. After the demonstration, students completed a survey to elicit information about students' level of training, prior experience with NGT placement, satisfaction with the AR technology, and perceptions of AR as a potential teaching tool for clinical skills training. Results The ability to correctly place the NGT through all the checklist items was statistically significant in the AR group compared with the control group (p = .011). Eighty-six percent of participants in the AR group rated AR as superior/far superior with other procedural training programs to which they had been exposed, whereas, only 5.9% of participants in the control group rated the control program as superior/far superior (p Conclusions Overall, the AR module was better received compared with the control group with regard to realism, identifying landmarks, visualization of internal organs, ease of use, usefulness, and promoting learning and understanding.

The hallmark of signalling by many cytokines is the activation of the Janus kinase (Jak)/signal transducer and activator of transcription (STAT) pathway. However, cytokines additionally activate other pathways. In past years we realised that these pathways significantly contribute to the physiological functions of IL-6 and pathophysiological functions in the context of many inflammatory and proliferative diseases. Whereas other articles in this issue of the European Journal of Cell Biology focus on STAT activation and its regulation we here aim to summarise our knowledge and some remaining questions on interleukin-6 (IL-6)-induced STAT-independent pathways as well as the cross-talk with the Jak/STAT pathway. In the early stages of studying cytokine signalling we were used to analysing individual signalling pathways. These days we know about the importance of both, the crosstalk between pathways initiated by combinations of cytokines as well as the crosstalk between individual pathways initiated by a single cytokine. Whereas the inter-cytokine crosstalk can be studied relatively easily, more sophisticated experimental approaches are required to elucidate the intra-cytokine crosstalk.

Glucocorticoids are known to be potent regulators of inflammation and have been used pharmacologically against inflammatory, immune, and lymphoproliferative diseases for more than 50 years. Due to their possible and well-documented side effects, it is crucial to understand the molecular mechanisms and targets of glucocorticoid action in detail. Several modes of action have been discussed; nevertheless, none of them fully explain all the functions of glucocorticoids. Therefore, we analyzed the cross-talk between glucocorticoids and interleukin-6 (IL-6) in the liver. IL-6 exerts pro-inflammatory as well as anti-inflammatory properties and is a main inducer of the acute-phase response. The balance between the proinflammatory and anti-inflammatory activities of IL-6 is tightly regulated by suppressor of cytokine signaling 3 (SOCS3), a well-known feedback inhibitor of IL-6 signaling. Here, it is demonstrated that glucocorticoids enhance IL-6–dependent γ-fibrinogen expression. Studying of the underlying mechanism revealed prolonged activation of signal transducer and activator of transcription 3 (STAT3) caused by down-regulation of SOCS3 protein expression. Consequently, in SOCS3-deficient cells glucocorticoids do not affect IL-6–induced signal transduction. Moreover, in hepatocytes lacking the SOCS3 recruiting motif within gp130, IL-6–dependent γ-fibrinogen expression is not influenced by glucocorticoid treatment. Conclusion: Glucocorticoids interfere with IL-6–induced expression of the feedback inhibitor SOCS3, thereby leading to enhanced expression of acute-phase genes in hepatocytes. This mechanism contributes to the explanation of how glucocorticoids affect inflammation and acute-phase gene induction. (HEPATOLOGY 2012;55:256–266)

Inflammation is the biological response to injurious stimuli. In the initial phase of the inflammatory process, interleukin-6 (IL-6) is the main inducer of acute phase protein expression in the liver. A prolonged acute phase response is characterised by a disturbed glucose homeostasis and elevated levels of IL-6, insulin, and counterregulatory hormones such as glucagon. Several studies deal with the impact of IL-6 on glucagon-dependent gene expression. In contrast, only very little is known about the influence of G-protein-coupled receptors on IL-6 signalling. Therefore, the aim of this study is to elucidate the regulation of IL-6-induced gene expression by glucagon. We could reveal a novel mechanism of negative regulation of IL-6-induced MAP kinase activation by glucagon in primary murine hepatocytes. IL-6-dependent induction of the ERK-dependent target gene Tfpi2, coding for a Kunitz-type serine protease inhibitor, was strongly down-regulated by glucagon treatment. Studying the underlying mechanism revealed a redundant action of the signalling molecules exchange protein activated by cyclic AMP (Epac) and protein kinase A. The metabolic hormone glucagon interferes in IL-6-induced gene expression. This observation is indicative for a regulatory role of G-protein-coupled receptors in the IL-6-dependent inflammatory response.

The transmembrane glycoprotein signal regulatory protein/SHP2-substrate (SIRP1alpha/SHPS-1) has been implicated in growth factor- and cell adhesion-induced signalling. Here we report on the contribution of SIRP1alpha to IL-6 type cytokine signalling. SIRP1alpha binds the protein tyrosine phosphatase SHP2 upon treatment with interleukin-6 in a stimulation-dependent manner. Mouse embryonic fibroblasts expressing a SIRP1alpha protein which lacks the intracellular part show enhanced SHP2 phosphorylation and ERK1/2 activation in response to IL-6, suggesting that SIRP1alpha affects IL-6-signalling through SHP2. Whereas SHP2 phosphorylation is enhanced in SIRP1alpha-deficient cells STAT3 activation is delayed and STAT3-dependent gene induction is reduced which correlates with reduced STAT3 serine phosphorylation. Our results indicate that SIRP1alpha contributes to IL-6 signalling by counteracting SHP2 phosphorylation which consequently affects ERK-activation and STAT3-dependent transactivation as well as target gene expression. Our observations will help to understand the tight balance of MAPK- and STAT3-activation in response to IL-6 which was found to be misbalanced in many autoimmune diseases, inflammatory proliferative diseases and cancer.

Misregulated interleukin-6 (IL-6)-induced Jak/STAT signaling contributes to many diseases. Under non-pathological conditions Jak/STAT signaling is tightly regulated by a complex network of regulators. One of these regulators is the protein tyrosine phosphatase SH2-containing phosphatase 2 (SHP2). Although SHP2 is known to be a negative regulator of IL-6-induced Jak/STAT signaling, its exact molecular function is not entirely understood. To elucidate the function of SHP2 in IL-6 signaling we followed a systems biology approach, in which modeling, stepwise model refinement, and experimental analysis are closely linked. We come up with an identifiable model of early Jak/STAT signaling that describes the data and proves to be predictive. The model-based analysis implies that (1) the stepwise association of IL-6 with gp80 and gp130 and (2) STAT3 dimerization at the receptor are essential for the dynamics of early pathway activation, and (3) phosphorylation of SHP2 is nonlinear. Furthermore, the modeling results indicate that SHP2 does not act as a feedback inhibitor in an early phase of IL-6-induced Jak/STAT signaling. However, experimental data reveal that SHP2 exhibits a basal repressory function.