Studies have focused on the events that influence the development of interleukin 17 (IL-17)-producing T helper cells (T(H)-17 cells) associated with autoimmunity, such as experimental autoimmune encephalitis, but relatively little is known about the cytokines that antagonize T(H)-17 cell effector responses. Here we show that IL-27 receptor-deficient mice chronically infected with Toxoplasma gondii developed severe neuroinflammation that was CD4+ T cell dependent and was associated with a prominent IL-17 response. In vitro, treatment of naive primary T cells with IL-27 suppressed the development T(H)-17 cells induced by IL-6 and transforming growth factor-beta, which was dependent on the intracellular signaling molecule STAT1 but was independent of inhibition of IL-6 signaling mediated by the suppressor protein SOCS3. Thus IL-27, a potent inhibitor of T(H)-17 cell development, may be a useful target for treating inflammatory diseases mediated by these cells.

Although previous studies have investigated the role of IL-27/WSX-1 interactions in the regulation of Th1 responses, little is known about their role in regulating Th2-type responses. Studies presented in this work identify a direct role for IL-27/WSX-1 interactions in the negative regulation of type 2 responses independent of effects on type 1 cytokines. WSX-1−/− mice infected with the gastrointestinal helminth Trichuris muris displayed accelerated expulsion of parasites and the development of exaggerated goblet cell hyperplasia and mastocytosis in the gut due to increased production of Th2 cytokines. Enhanced mast cell activity in the absence of WSX-1 was consistent with the ability of wild-type mast cells to express this receptor. In addition, IL-27 directly suppressed CD4+ T cell proliferation and Th2 cytokine production. Together, these studies identify a novel role for IL-27/WSX-1 in limiting innate and adaptive components of type 2 immunity at mucosal sites.

The recent identification of IL-27 (IL-27p28/EBV-induced gene 3) and IL-27R (WSX-1/gp130) has provided new insights for the biology of IL-6/IL-12 family cytokines. Initial studies indicated that IL-27 can directly regulate T cell functions and suggested an important role for it in promoting Th1 type responses. However, subsequent studies have revealed that IL-27R signaling influences a variety of immune cell types and can inhibit either Th1 or Th2 type responses. Though elucidation of the Jak/STAT signaling pathways activated by IL-27R ligation has unveiled some of the molecular mechanisms used by IL-27 to promote inflammation, little is known about the anti-inflammatory activities of this cytokine. Thus, the aim of this review is to discuss the pleotropic nature of the IL-27/IL-27R interaction and attempt to reconcile the pro- and anti-inflammatory properties of this immunomodulator.

BackgroundOpioids and benzodiazepines are frequently used in the intensive care unit (ICU). Regular use and prolonged exposure to opioids in ICU patients followed by abrupt tapering or cessation may lead to iatrogenic withdrawal syndrome (IWS). IWS is well described in pediatrics, but no prospective study has evaluated this syndrome in adult ICU patients. The objective of this study was to determine the incidence of IWS caused by opioids in a critically ill adult population. This multicenter prospective cohort study was conducted at two level-1 trauma ICUs between February 2015 and September 2015 and included 54 critically ill patients. Participants were eligible if they were 18 years and older, mechanically ventilated and had received more than 72 h of regular intermittent or continuous intravenous infusion of opioids. For each enrolled patient and per each opioid weaning episode, presence of IWS was assessed by a qualified ICU physician or senior resident according to the 5th edition of Diagnostic and Statistical Manual of Mental Disorders criteria for opioid withdrawal.ResultsThe population consisted mostly of males (74.1%) with a median age of 50 years (25th–75th percentile 38.2–64.5). The median ICU admission APACHE II score was 22 (25th–75th percentile 12.0–28.2). The overall incidence of IWS was 16.7% (95% CI 6–27). The median cumulative opioid dose prior to weaning was higher in patients with IWS (245.7 vs. 169.4 mcg/kg, fentanyl equivalent). Patients with IWS were also exposed to opioids for a longer period of time as compared to patients without IWS (median 151 vs. 125 h). However, these results were not statistically significant.ConclusionsIWS was occasionally observed in this very specific population of mechanically ventilated, critically ill ICU patients. Further studies are needed to confirm these preliminary results and identify risk factors.

Matrix ligation of integrins ␣v␤3/␣v␤5 is critical for endothelial survival and angiogenesis. We have previously shown that ceramide, a proapoptotic lipid second messenger, increases during endothelial anoikis (detachment-induced apoptosis). We now show that RGDfV, an integrin ␣v␤3/␣v␤5 cyclic function-blocking peptide, increased ceramide and decreased sphingomyelin in human brain microvascular endothelial cells (HBMECs) plated on vitronectin, suggesting that sphingomyelin hydrolysis contributes to RGDfVinduced ceramide increase. Desipramine and imipramine, inhibitors of acid sphingomyelinase (ASMase), suppressed RGDfV-induced ceramide increase. Importantly, desipramine, imipramine, and a third ASMase inhibitor, SR33557, but not inhibitors of neutral sphingomyelinase, suppressed RGDfV-induced apoptosis, suggesting that ASMase was required for integrin-mediated apoptosis. Myriocin, an inhibitor of de novo ceramide synthesis, had no effect on RGDfV-induced HBMEC apoptosis. Interestingly, ASMase inhibitors also suppressed the RGDfV-induced loss of spreading on vitronectin. RGDfV IntroductionIntegrins are heterodimeric cell-surface receptors composed of ␣ and ␤ subunits. Integrins regulate functions such as cell movement, gene expression, cell cycle regulation, and cell survival, using complex signaling cascades with both inside-out as well as outside-in signaling. [1][2][3][4] Integrins ␣v␤3 and ␣v␤5 are preferentially expressed on angiogenic endothelial cells, and their inhibition induces apoptosis. [5][6][7][8][9] The signal mediated by ␣v␤3 and ␣v␤5 requires their binding to matrix proteins such as vitronectin, fibronectin, osteopontin, and tenascin. This binding is via arginineglycine-aspartic acid (RGD) sequences and can be specifically abrogated by function-blocking cyclic RGDfV peptides containing this sequence. 10 In vivo, inhibition of integrins ␣v␤3 and/or ␣v␤5 results in suppression of new blood vessel formation, disruption of existing angiogenic vasculature, inhibition of tumor growth, and tumor regression, [5][6][7][8][11][12][13] providing rationale for inhibition of integrins ␣v␤3 and ␣v␤5 in antiangiogenic therapy. Indeed, one of the cyclic RGDfV peptides (cilengitide, EMD 121974), monoclonal antibodies, and other inhibitors of integrins ␣v␤3 and/or ␣v␤5 are currently in clinical trials that attempt to harness their antiangiogenic potential. [14][15][16][17] Integrin ␣v␤3/␣v␤5 signaling regulates migration, proliferation, and survival of endothelial cells, thereby affecting angiogenesis. Signaling from integrin ␣v␤3 leads to inhibition of p53 transcriptional activity, decreased expression of p21 WAF1/CIP1 , and suppression of the bax cell death pathway in endothelial cells. 12 However, as demonstrated in wild-type and p53-null mice, inhibition of ␣v-integrin ligation in developing retinas induces p21 WAF1 independently of p53, underscoring the complexity and diversity of this pathway. 18 On osteopontin, the ␣v␤3-dependent signals for endothelial cell survival are mediated via nuclear factor B (NF-B...