Erythropoietin does not affect TNF and IL-6 production directly.

The tissue-protective action of erythropoietin (EPO) in animal models is often associated with reduced inflammation. However, there are many contrasting reports of the effect of EPO on the production of inflammatory cytokines induced by lipopolysaccharide (LPS) in vitro, with different papers reporting an inhibition, an upregulation, or a lack of effect. Negative results are likely underestimated by a publication bias. As EPO has anti-inflammatory actions in models associated with tissue injury, we hypothesized that EPO could specifically inhibit the induction of inflammatory cytokines by danger signals associated with cell death, and investigated its effect on the induction of IL-6 or TNF by high-mobility group-box 1 protein (HMGB1) or by necrotic cells. We did not observe any significant effect of EPO in these models; neither EPO affected the response induced by TLR agonists different from LPS, or by extracellular ATP-mediated activation of the inflammasome. We conclude that the inhibition of inflammation by EPO is likely to be an indirect effect, secondary to its tissue-protective activity, or that it requires a prior priming induced by the injury.

Targeting Toll-like receptors in autoimmunity.

In the past few years there has been an increasing appreciation of the importance of Toll-like receptors (TLRs), not just in immunity, but also in autoimmune diseases. TLRs were first identified as sensors of viral and bacterial pathogens that form an integral part of the innate immune response. It was later discovered that these receptors can also respond to endogenous ligands that are produced as a result of tissue damage. This lead to the hypothesis that TLRs may be key contributors to the pathogenesis of chronic inflammatory conditions. A large body of data supporting the role of TLRs in autoimmunity has emerged from animal models and more data is increasingly being generated from human studies as further tools to examine these receptors have become available. Developing strategies to manipulate TLR function is of great interest in autoimmunity, as well as other diseases that include allergy and cancer. This review explores the evidence that points to a role for TLRs in autoimmunity and highlights some of the potential ways in which modulation of their action may yield clinical benefits.

Induction of TLR tolerance in human macrophages by adiponectin: does LPS play a role?

Obesity is regarded as a pro-inflammatory state. It is associated with low circulating levels of the adipokine, adiponectin, which is considered to be an anti-inflammatory. However, adiponectin knockout mice do not consistently demonstrate pro-inflammatory phenotypes, suggesting more complexity in the in vivo immunomodulatory effects of adiponectin than originally anticipated. Moreover, adiponectin exerts pro-inflammatory effects in some experimental systems. This contradiction has been resolved by hypothesizing that adiponectin induces tolerance to inflammatory stimuli, notably Toll-like receptor (TLR) ligands. We noticed that this effect resembled lipopolysaccharide (LPS) tolerance and therefore tested adiponectin from a variety of sources for LPS contamination. All adiponectin tested carried low levels of LPS in the range of 1-30 pg/microg of adiponectin, sufficient to produce final LPS concentrations in the pg/ml range under experimental conditions. We found that induction of tolerance to TLR ligands by adiponectin in human monocyte-derived macrophages could be reproduced by such LPS concentrations. Moreover, the LPS antagonist, polymixin B, substantially inhibited induction of tolerance by adiponectin. Furthermore, polymixin B and a naturally occurring antagonist LPS were able to partially attenuate induction of tumour necrosis factor-alpha and interleukin-6 in human monocyte-derived macrophages by adiponectin. Polymixin B also inhibited nuclear factor-kappaB and mitogen-activated protein kinase signalling elicited by adiponectin. We therefore propose that some of adiponectin's immunomodulatory effects, in particular, its TLR-tolerising actions in human monocyte-derived macrophages, may be confounded by induction of tolerance by contaminating LPS.

Is NF-kappaB a useful therapeutic target in rheumatoid arthritis?

There is increasing evidence that NF-kappaB is a major, if not the major transcription factor regulating inflammation and immunity. While this implies that blocking NF-kappaB might be therapeutically beneficial, it raises clear questions regarding the balance between efficacy and safety. In this brief review we discuss the effects of NF-kappaB blockade in rheumatoid arthritis, inflammation and immunity, and consider possible therapeutic targets within the NF-kappaB family.

Cell-derived apolipoprotein E (ApoE) particles inhibit vascular cell adhesion molecule-1 (VCAM-1) expression in human endothelial cells.

Sub-endothelial infiltration of monocytes occurs early in atherogenesis and is facilitated by cell adhesion molecules that are up-regulated on activated endothelium. Apolipoprotein E (apoE) helps protect against atherosclerosis, in part, because apoE particles secreted by macrophages have local beneficial effects at lesion sites. Here, we hypothesize that such protection includes anti-inflammatory actions and investigate whether cell-derived apoE can inhibit tumor necrosis factor-alpha-mediated up-regulation of vascular cell adhesion molecule-1 (VCAM-1) in human umbilical vein endothelial cells (HUVECs). Two models were used to mimic endothelial exposure to macrophage-derived apoE. In the first, HUVECs were transiently transfected to secrete apoE; VCAM-1 induction inversely correlated with secretion of apoE into the media (r = -0.76, p < 0.001). In the second, incubation of HUVECs with media from recombinant Chinese hamster ovary (CHO) cells expressing apoE (CHO(apoE)) also reduced VCAM-1 in a dose-dependent manner (r = -0.70, p < 0.001). Characterization of CHO(apoE) cell-derived apoE revealed several similarities to apoE particles secreted by human blood monocyte-derived macrophages. The suppression of endothelial activation by apoE most likely occurs via stimulation of endothelial nitric oxide synthase; apoE increased levels of intracellular nitric oxide and its surrogate marker, cyclic guanosine monophosphate, while the nitric oxide synthase inhibitor, ethyl-isothiourea, blocked its effect. We propose that apoE secreted locally at lesion sites by macrophages may be anti-inflammatory by stimulating endothelium to release NO and suppress VCAM-1 expression.

Audio presence intervention for decreasing agitation in people with dementia.

Researchers have demonstrated the utility of various nonpharmacologic interventions in decreasing or preventing agitation in elderly nursing home residents with dementia. Auditory intervention strategies are one behavioral approach. We tested a modified version of simulated presence therapy called audio presence intervention (API). In 28 episodes of agitation among seven residents, API produced a significant decline in agitation level as measured by four items from the Haycox Rating Scale. However, in six episodes (four residents), agitation stayed the same or worsened. The results of this study pose more questions than answers and should stimulate nurse researchers to further investigate auditory intervention for control of agitation elders with dementia.

Continuous administration of fentanyl for postoperative pain: a comparison of the epidural, intravenous, and transdermal routes.

STUDY OBJECTIVES: To evaluate the influence of the route of administration [epidural, intravenous (IV), or transdermal] on onset and quality of analgesia and to evaluate the pharmacokinetics of continuous administration of fentanyl. DESIGN: Randomized, open, single-dose, prospective study. SETTING: Postanesthesia care unit of a university hospital. PATIENTS: 54 ASA physical status I-III patients scheduled for lower major abdominal, gynecologic, or urologic surgery. INTERVENTIONS: Patients were assigned to 1 of 3 comparable groups, to receive, for 72 hours postoperatively, an IV (Group IV) or epidural (Group EP) constant-rate infusion of fentanyl (loading dose 1.5 micrograms/kg, infusion rate 1 micrograms/kg/hr), or a transdermal patch (Group TTS), applied preoperatively, delivering fentanyl 75 micrograms/hr. MEASUREMENTS AND MAIN RESULTS: Pain intensity, vital signs, blood gas status, and plasma fentanyl concentration (Cp) were measured for up to 96 hours postoperatively. Onset of analgesia was delayed in Group TTS. Analgesic efficacy was similar for all 3 routes of administration except during the first 4 hours in Group TTS. Initially, the patients in Groups TTS and IV needed significantly more rescue morphine than those in Group EP. The time course for fentanyl Cp in Groups TTS and IV evolved to similar plateau levels. However, fentanyl Cp continued to rise throughout the study period in Group EP, reaching concentrations that elicited hypoxemia after 48 hours. A significant negative relationship existed between fentanyl Cp and oxygen saturation in this group. All 3 routes of administration showed similar frequencies of side effects (i.e., nausea, vomiting, pruritus, and ileus). CONCLUSIONS: The epidural, transdermal, and IV administration of identical doses of fentanyl given at a constant rate provided almost equivalent degrees of analgesia. But continuing epidural administration produced a steady rise in systemic fentanyl concentrations into the ventilatory-depressant range, affecting the hypoxemic regulation of breathing.