The patients were grouped into the following categories: International Federation of Gynecology and Obstetrics (FIGO) stage IB (n = 16) and stage IIA–IIIB (n = 24). All tissues were subjected to immunohistochemical staining for IL-32 as described previously27

and clinically correlated with FIGO stage and survival, and the following results were obtained. In the serial section, immunohistochemical staining for COX-2 was also conducted to determine whether IL-32 and COX-2 are co-localized in cervical cancer cells. This study was approved by the Chungnam National University Hospital. The IL-32γ and COX-2 were amplified from the genomic DNA of human CaSki cells via PCR, using the following primers, respectively: IL-32γ: 5′-CTGGAATTCATGTGCTTCCCGAAG-3′ (forward), 5′-GAAGGTCCTCTCTGATGACA-3′ (reverse); COX-2: 5′-CCCAAGCTTGGGCTCAGACAGCAAAGC CTA-3′ (forward), 5′-CTAGTCTAGACTAGCTACAGTTCAGTCGAACGTTCTTT-3′ (reverse). Interleukin-32γ Ferroptosis targets https://www.selleckchem.com/products/Romidepsin-FK228.html was cloned into the EcoRI and XhoI sites of pCDNA3.1 using EcoRI and SalI, and COX-2 was ligated with pCDNA3.1 vector using the HindIII and XbaI sites. The promoters of IL-32 and COX-2 were amplified via PCR from human genomic DNA. The IL-32 promoter (−746/+25) was constructed as previously reported.21 The COX-2 promoter (−880/+9) used the following primers: 5′-CGGGATCCAAATTCTGGCCATCGCCGCTT-3′ (forward), 5′-CCAAGCTTTGACAATTGGTCGCTAA

CCGAG-3′

(reverse) cloned into the MluI and HindIII sites of the pGL3-basic vector, and the inserted sequences were confirmed via DNA sequencing. Both pTarget/E7 and pTarget/E7 antisense (E7AS) were described in a previous report.25,28 C33A/pOPI3, C33A/E7, SiHa and CaSki cells were seeded on six-well plates at a density of 3 × 105 cells per well, then grown to confluence, reaching approximately 80% at the time of transfection. For each well, plasmid DNA (1 μg) was introduced into the cells using an identical volume of Lipofectamine 2000 reagent (Invitrogen, Carlsbad, CA) in accordance with the manufacturer’s instructions. The pTarget Molecular motor and pTarget/E7AS plasmid were transfected into C33A/E7, SiHa and CaSki cells to confirm the E7 oncogene-specific effect on IL-32 and COX-2 expression in HPV-expressing cervical cancer cells. The pGL3 basic, pGL3b/IL-32 promoter, and pGL3b/COX-2 promoter were respectively co-transfected with pTarget, pTarget/E7 and pTarget/E7AS into C33A/pOPI3, C33A/E7, SiHa and CaSki cells to determine the specific effects of E7 on the transcriptional activities of IL-32 and COX-2. Additionally, pCDNA3.1, pCDNA3.1/COX-2, pCDNA3.1/IL-32γ, siCONTROL and siIL-32 (Dharmacon, Lafayette, CO) were respectively transfected into SiHa and CaSki cells to evaluate expression between COX-2 and IL-32 by the HPV E7 oncogene. Interleukin-32γ is the most active form of IL-32 isoforms.

In African populations, the frequency of KIR2DS5, in parallel with the remaining telomeric B haplotype genes (KIR3DS1 and KIR2DS1) with which it is generally associated, is extremely low. In contrast, ITF2357 datasheet KIR2DS5 is almost always observed in Amerindian populations regardless of whether the locus is centromeric or telomeric in the KIR region and KIR2DS3 is largely absent in these populations.112,115,130 Notably, whereas KIR2DS3 is rarely seen in Amerindian populations, it is observed at moderate frequencies in East Asian populations, suggesting that the fixation of the KIR2DS5 allele at these loci occurred in conjunction with or subsequent to the New World migration and

divergence of Amerindian populations. Meta-analyses of populations gathered worldwide from publications and the http://www.allelefrequencies.net Raf tumor database131 have shown that KIR polymorphism is correlated to geography,6,119,132 despite some limitations

in the anthropological characterization of these data. For instance, gene presence/absence frequencies at activating loci (i.e. DS genes) and inhibitory loci (i.e. DL genes) linked to KIR haplotype B clearly reflect a geographical gradient among populations.133 However, the same study on inhibitory loci linked to KIR haplotype A did not show such a correlation. It is important to note that these meta-analyses are based on KIR gene content only, and do not take allelic variation into Thiamet G account, which may explain the different patterns observed between A and B haplotypes. Indeed, because of the polymorphism peculiarities of both haplotype groups (see above), gene content polymorphism for B-related loci appear to be sufficiently discriminative for population genetic comparisons, whereas similar analyses on A-related loci may rely on allelic typing. The study of a limited number of populations where KIR variations were examined at the allele level appears to corroborate this

hypothesis.132 In light of these studies, KIR genes appear to be good markers for anthropological studies, similar to the polymorphisms of GM and HLA genes, and mtDNA and Y chromosome markers. However, more in-depth analyses, notably at the allelic level and including more populations with more thorough anthropological characterization, must be achieved to confirm this. In addition to demographic factors and stochastic forces such as gene flow and genetic drift, KIR diversity is thought to have been shaped by various selective forces. The KIR inhibitory and activating receptors, among others, regulate NK cell functions134 and KIR gene content has been associated with infection, cancer, autoimmunity, pregnancy syndromes, and transplant outcome. These features are likely to make KIR a good candidate for ongoing adaptive evolution.

Suzuki et al.9 observed that ddY mice could be classified into three groups – the early-onset (<20 weeks), late-onset (−40 weeks) and quiescent groups – by serial renal

biopsies that confirm glomerular lesions and IgA deposition. A genome-wide association study of the early-onset and the quiescent mice revealed that the susceptibility to murine IgA nephropathy is partly regulated by specific loci syntenic to the IgAN1 LY2157299 datasheet gene known as a candidate gene of human familial IgA nephropathy.9,10 These results indicated the suitability of the grouped ddY mouse model for studying the pathogenesis of IgA nephropathy. Although the potential of bone marrow derived cells (BMC) to differentiate to glomerular cells has been discussed, the role of BMC in the kidney is still obscure. The mechanism of glomerular immune-complex deposition and the role of BMC in the kidneys were examined using ddY mice. In 2007, Suzuki et al.27 also

reported that BMC are responsible for the induction of IgA nephropathy. BMT from early-onset ddY mice resulted in mesangioproliferative Trametinib molecular weight glomerular injury with mesangial IgA and IgG depositions in recipient-quiescent ddY mice. In contrast, BMT from quiescent ddY mice resulted in reduction of not only glomerular injury but also mesangial IgA and IgG depositions in recipient early-onset ddY mice. BMT from early-onset ddY mice caused progression of urinary albumin levels in recipient quiescent ddY mice, and also caused a marked increase of urinary albumin levels in recipient early-onset ddY mice. It appears that BMC, presumed to be IgA producing cells, may initiate IgA nephropathy. Th1 cells may be involved in the pathophysiology of the disease after glomerular IgA Tacrolimus (FK506) deposition.27 I sincerely thank my colleagues in the Division of Nephrology, Department of Internal Medicine at Juntendo University Faculty of Medicine, Tokyo, Japan. “
“Aim:  The mortality and morbidity of end-stage renal failure patients remains

high despite recent advances in pre-dialysis care. Previous studies suggesting a positive effect of pre-dialysis education were limited by unmatched comparisons between the recipients and non-recipients of education. The present study aimed to clarify the roles of the multidisciplinary pre-dialysis education (MPE) in chronic kidney disease patients. Methods:  We performed a retrospective single centre study, enrolling 1218 consecutive pre-dialysis chronic kidney disease patients, between July 2007 and Feb 2008 and followed them up to 30 months. By using propensity score matching, we matched 149 recipient- and non-recipient pairs from 1218 patients. The incidences of renal replacement therapy, mortality, cardiovascular event and infection were compared between recipients and non-recipients of MPE. Results:  Renal replacement therapy was initiated in 62 and 64 patients in the recipients and non-recipients, respectively (P > 0.05).

MHC class I tetramers specific for NP118 and GP283 were prepared using published protocols [[58, 59]]. Significant differences between two groups were evaluated using a two-tailed Student’s t-test. We sincerely thank all members of the Harty laboratory for helpful discussion. Supported by NIH grants AI46653, AI150073, and AI42767. The authors declare no commercial or financial conflicts of interest. “
“Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston,

MA, USA Astragalus polysaccharides (APS), extracted from the root of Astragalus membranaceus, a traditional Chinese medicinal herb, have extensive pharmacological and strong immunomodulatory effects. In this study, the potential adjuvant effect of APS on humoral and cellular immune responses to hepatitis B subunit vaccine was investigated. FDA-approved Drug Library Coadministration of APS check details with recombinant hepatitis B surface antigen significantly increased antigen-specific antibody production, T-cell proliferation and CTL (cytotoxic T lymphocyte) activity. Production of interferon-γ (IFN-γ), interleukin-2 (IL-2) and IL-4 in CD4+T cells and of IFN-γ in CD8+T cells were dramatically increased. Furthermore, expression of the genes PFP, GraB, Fas L and Fas were up-regulated; interestingly, expression of transforming growth factor

β (TGF-β) and the frequency of CD4+CD25+Foxp3+ regulatory T cells (Treg cells) were down-regulated. Expression of Toll-like receptor 4 (TLR4)

was significantly increased by administration of APS. Together, these results suggest that APS is a potent adjuvant for the hepatitis B subunit vaccine and can enhance both humoral and cellular immune responses via activating the TLR4 signaling pathway and inhibit the expression of TGF-β and frequency of Treg cells. Hepatitis B is a potentially life-threatening liver disease caused by hepatitis B virus (HBV) infection. It is a global health problem and the most serious type of viral hepatitis (Chisari & Ferrari, 1995). More than 350 million people worldwide are chronic HBV carriers, and 1–2 million people die each year due to the consequences of chronic hepatitis B (Rehermann, 2005). To date, the commercial recombinant hepatitis B surface antigen (HBsAg) vaccine has been widely used, and has become an effective strategy for preventing HBV MYO10 infection. However, the vaccine primarily induces the antibody response and Th2-biased immune response, but elicits relatively weak cell-mediated immune responses, particularly the antigen-specific CTL response. Therefore, it is unable to clear the virus in the infected cells (Zhang et al., 2009; Geurtsvan et al., 2008). Astragalus membranaceus (Huangqi) is a well-tolerated and nontoxic traditional medicinal herb that is used as a therapeutic agent to treat many diseases in China (Luo et al., 2009; Cui et al., 2003). Astragalus polysaccharides (APS), the major component in the root of A.

g. genes encoding products in a same metabolic pathway) at the top or bottom of a ranked list of genes L. Candidate genes are ranked by their differential expression between two phenotypes. The statistic is a weighted Kolmogorov-Smirnov-like statistic and significance is calculated using an empirical permutation test [13]. Here we applied an extended version of conventional GSEA in order to produce an enrichment score in a single sample as we have previously [14]. Such a score is necessary if one is to make a predictive call on single samples Selleck Autophagy inhibitor without reference to a larger group of samples. In this approach, the genes are ordered based on either absolute

expression (as in the yellow fever vaccine study) or the relative changes with respect to the baseline level (as in the influenza TIV vaccine

study). In this study, we used C2 collection from Molecular Signature Database (MsigDB). The MsigDB is a publicly available database of annotated gene sets hosted at Broad Institute (http://www.broadinstitute.org/gsea/msigdb/index.jsp) [11]. Currently, there are six major collections from C1 to C6 while C2 is a special collection of gene sets carefully curated selleck screening library from online pathway databases, publications in PubMed, and knowledge of domain experts. Each of the ∼3000 gene sets in C2 collection is well described in the MsigDB website including the source, annotation as well as other useful information, thus facilitate the interpretation of the biological meaning associated with it.

To detect gene sets whose enrichment scores are highly correlated with phenotypes, we used a normalized mutual information (NMI) score (Eq. (3)) to evaluate the association between phenotypes (day 7 versus day 0 in the yellow fever vaccine study; or high versus low HAI antibody response in the influenza TIV vaccine study) and gene set enrichment scores. (1) The constellation plot is designed to visualize and Enzalutamide cost thus to elucidate groups of gene sets enriched in a phenotype of interest (e.g. vaccine response) that correspond to distinct biological processes. We reasoned that gene sets that (i) demonstrate high mutual information with respect to the phenotype; (ii) demonstrate high mutual information with respect to each other; and (iii) share overlapping member genes would be likely to reflect similar biological processes. We estimated similarities between N gene sets using an NMI score and further transformed it into a dissimilarity score, d = 1 – NMI. Previous studies [29] have proved that this dissimilarity metric has all the properties of a true mathematical distance (metric), allowing us to represent the association of gene sets with a proper distance matrix D. We visualized this distance matrix D as a radial plot in which the angle between two gene sets represents the distance d between them, and their proximity to the center reflects their differential enrichment with respect to the phenotype (1 – NMI).

In the presence of the TCR signal, CpG-ODN induces IL-2 production, IL-2R expression and thus T cell proliferation. Furthermore, CpG-co-stimulated T cells differentiate into cytolytic T lymphocytes in vitro[54]. Naive human T cells express

high levels of cell-surface TLR-2 after activation by anti-TCR antibody and interferon (IFN)-α. Activated cells produce more cytokines in response to the TLR-2 ligand, bacterial lipopeptide [44]. Furthermore, memory human CD4+CD45RO+ T cells express TLR-2 constitutively and produce IFN-γ in response to bacterial lipopeptide [44]. Co-stimulation of antigen-activated murine CD8+ T cells with the lipopeptide Pam3CysSK4 (Pam), a TLR-1/2 ligand, enhances the proliferation, survival and effector functions ACP-196 concentration of these cells [54]. TLR-2 engagement on CD8+ T cells reduces significantly their need for co-stimulatory signals delivered usually by mature APCs [39].

Importantly, human T cells were also reported to respond similarly to the endogenous ligand HSP60 through TLR-2, although these results could reflect potential contamination of commercially available HSP60 with bacterial TLR-2 ligands [55]. T cells responding to endogenous TLR ligands is intriguing, because it opens the possibility that DAMPs may potentially support T cell responses at sites of damaging tissue. It should be noted that TLR ligands do not induce functional responses in T cells in the absence of concurrent TCR stimulation [11], indicating that TLR-induced signals in T cells are strictly co-stimulatory, which may be important buy Rapamycin for preventing TLR signal-mediated non-specific T cell activation. On the other hand, LPS treatment results in increased adhesion of mouse and human T cells to fibronectin and inhibited chemotaxis [56]. Thus, in addition to functioning as potential co-stimulatory CHIR-99021 manufacturer molecules, TLRs may also play

a role in controlling T cell trafficking. Naturally occurring and antigen-induced CD4+CD25+ Treg cells have been studied extensively in mice and humans. Depletion of the naturally occurring subset of CD4+CD25+ Treg cells results in various types of autoimmune diseases [57,58]. TLR ligands modulate CD4+CD25+ Treg cell responses indirectly by promoting inflammatory cytokine production in APCs, which can inhibit the suppressive capacity of CD4+CD25+ Treg cells [59]. However, some TLRs are expressed on CD4+CD25+ Treg cells. It has been reported that naive CD4+CD25+ Treg cells express TLR-4, -5, -7 and -8 selectively, whereas TLR-1, -2, -3 and -6 appear to be expressed more broadly on CD4+ T cells, but not confined to CD4+CD25+ Treg cells [10]. The distinct expression pattern of TLRs on CD4+CD25+ Treg cells supports the potential involvement of these TLRs in the direct regulation of CD4+CD25+ Treg cells [9,60]. It has been shown that ligands for TLR-2, -5 and -8 modulate the proliferation and suppressive functions of CD4+CD25+ Treg cells.

8 Previous studies have

revealed that inflammatory mediators find protocol influence the apoptosis of inflammatory cells.9,10 However, the literature concerning the effect of inflammatory modulators on phagocytic clearance of apoptotic cells is limited and contains discrepancies. For example, TNF-α, a key pro-inflammatory factor that is up-regulated at inflammatory sites, has been reported previously to enhance the uptake of apoptotic cells by immature monocyte-derived macrophages.11 Another study demonstrated that TNF-α inhibits the phagocytosis of apoptotic cells by mature macrophages.12 A recent study indicated that the uptake of apoptotic neutrophils by human monocyte-derived macrophages was negatively regulated by TNF-α, which was opposite to the effect of the anti-inflammatory factor interleukin (IL)-10.13 Growth arrest-specific gene 6 (Gas6) is an anti-inflammatory factor.14,15 Gas6 and its receptors – Tyro3, Axl and Mer (TAM) receptor tyrosine kinases– are broadly expressed in various types of phagocyte. The activation of TAM receptors by Gas6 inhibits inflammation responses and promotes the phagocytosis of apoptotic cells by phagocytes.16 In the present study, we found that LPS specifically inhibited mouse macrophage uptake of apoptotic neutrophils through suppression

of Gas6 and induction of TNF-α in an autocrine manner. The findings provide novel insights into the effect of inflammatory modulators on phagocytic clearance of

apoptotic cells by macrophages. C57BL/6J mice were selleck products purchased from the Laboratory Animal Center of Peking Union Medical College (Beijing, China). Toll-like receptor 4 (TLR4) mutant C57BL/10ScN mice (Cat. 003752) were this website purchased from Jackson Laboratories (Bar Harbor, ME). The animals were housed under specific pathogen-free conditions with a 12-hr light/dark cycle and had free access to food and water. The mice were maintained and treated in accordance with the guidelines for the care and use of laboratory animals established by the Chinese Council on Animal Care. Mice 8–10 weeks old were used in this study. Ultrapure LPS (Escherichia coli 0111:B4) was obtained from InvivoGen (San Diego, CA), and no detectable TNF was produced in TLR4-null (TLR4−/−) macrophages in response to this LPS. TNF-α and neutralizing antibodies against TNF-α were obtained from PeproTech Inc. (Rocky Hill, NJ). Gas6 and neutralizing antibodies against Gas6 were obtained from R & D Systems (Minneapolis, MN). Peritoneal macrophages were collected from peritoneal fluid as previously described.17 Briefly, mice were anaesthetized with CO2 and then killed by cervical dislocation. The peritoneal cavities were lavaged with 5 ml of cold phosphate-buffered saline (PBS) to collect peritoneal cells. The cells were seeded at 4 × 105 cells/well into a 24-well plate with RPMI-1640 medium (Gibco-BRL, Grand Island, NY) containing 10% fetal calf serum (FCS; Gibco-BRL).

The third difficulty is that many BKVN cases show tubulointerstitial

inflammation mimicking T-cell mediated acute rejection, which is another cause of misdiagnosis. Interpretation of the inflammation is still under debate; concurrent acute rejection, or Vadimezan clinical trial inflammation as an anti-viral immune response. The relationship between viral infection and rejection is known to be bi-directional: viral infection can trigger rejection or vice versa. Recent studies suggest that putative episodes of acute rejection develop at the same time or after the onset of viruria.[22, 23] In the setting of sustained BK viruria, biopsies with rejection-like episodes that satisfy Banff criteria for diagnosis do not always respond to steroids,[23] suggesting the inflammatory response is induced by BKV. In addition, with regard to biopsy samples of BKVN, Menter et al. reported that tissue obtained in the decreasing phase of the plasma selleck kinase inhibitor BK viral load showed more severe interstitial infiltrates and tubulitis,[24] suggesting that the immune response that facilitates the clearance

of the virus from tissues might cause self-limiting tubulointerstitial nephritis. It is currently thought that inflammation from viral or allograft antigens cannot be reliably distinguished by light microscopy. Although several molecules have been reported to be markers for distinguishing BKVN and rejection,[25-27] they are not yet in clinical application. Further study is required to identify molecular markers in biopsy tissues, urine or blood samples that distinguish the cause of inflammation easily in routine practice. The ability to predict the clinical outcome in individual patients is important in BKVN. Clinical factors reported to be associated

with a poor prognosis include deceased donor, female recipient, high serum creatinine, serum creatinine increase from baseline, late diagnosis and plasma viral load.[14, 28-30] As BKVN is ultimately a pathological diagnosis, there has been much interest in exploring the effects of histologic variables on the course of the disease. The old percentage of tubular cross-sections showing infection and degree of interstitial fibrosis and tubular atrophy was identified as important in an early study.[30] A composite system to stage the disease based on viral cytopathic effect, extent of inflammation and severity of fibrosis was first proposed by Drachenberg et al. (University of Maryland schema),[11] and AST has published variations of this schema (AST schema).[9, 10] The Banff Working Group also proposed a staging system in 2009, which places emphasis on the extent of virus-induced tubular epithelial injury as measured by necrosis, cell lysis, shedding into the tubular lumen, and denudation of tubular basement membranes (Banff Working Proposal).[12, 13] The three staging systems are summarized in the Table 1.

Methods: Mouse model of diabetic nephropathy was made by administration of streptozotocin onto endothelial nitric oxide knockout mice (eNOS−/−) as reported previously (4). In order to obtain animals with reduced selleck chemicals expression of TonEBP, TonEBP haploinsufficient mice (TonEBP+/Δ, heterozygotes) (5) were bred on the eNOS−/− background. Results: We found that hyperglycemia induced pro-inflammatory activation of macrophages. This was mediated by enhanced expression of TonEBP, which stimulated pro-inflammatory

gene expression by way of enhancing the NFκB activity. TonEBP was an integral component of the NFκB enhancesome as it was necessary for recruitment of transcription cofactors. In the diabetic animals, pro-inflammatory gene expression in the macrophages was significantly reduced in the TonEBP heterozygotes. In the kidney, fewer macrophages were found in the heterozygotes in association with reduced

expression of pro-inflammatory Palbociclib genes including IL-6, MCP-1, IP-10, IL-8, TNFα, IL-1β1, IL-18 and RANTES. As could be expected from the reduced IL-6 expression, STAT3 phosphorylation was lower in the kidney. Parameters of diabetic nephropathy – proteinuria, glomerular sclerosis, and interstitial fibrosis – all decreased in the TonEBP heterozygotes. Renal expression of TGF-β also decreased in the heterozygotes in keeping with the reduced fibrosis. Conclusion: Taken together, these data demonstrate that exacerbation of diabetic nephropathy with higher level of TonEBP expression observed in patients (1) is reproduced in the mouse model. The data provide mechanistic insight that TonEBP-mediated macrophage activation in response to hyperglycemia leads to

renal inflammation and diabetic nephropathy. 1. Diabetes 55: 1450–1455, 2006 2. J Exp Med 209: 379–393, 2012 3. Frontiers Physiol 3: 313, 2012 4. J Am Soc Nephrol 18: 539–550, 2007 5. Proc Natl Acad Sci USA 101: 10673–10678, 2004 WU HUILING1,2, MA JIN1, CHEN XIAOCHEN1, STRIBOS ISABEL1, MESSCHENDORP LIANNE1, ZHAO CATHY1, PAUL MOUMITA1, CUNNINGHAM EITHNE1, SHARLAND ALEXANDRA1, CHADBAN STEVEN1,2 1Collaborative Transplant Research Group, University of Sydney; 2Renal Medicine, Royal Prince Alfred Hospital Introduction: We have reported that activation of TLR2 or tuclazepam 4 by their endogenous ligands (eg. HMGB1) mediates diabetic kidney injury. esRAGE is a soluble decoy receptor that can competitively bind ligands for TLRs/RAGE, including HMGB1. Here we test the hypothesis that blocking the interaction between TLRs/RAGE and HMGB1 will attenuate kidney injury in STZ induced diabetic nephropathy (DN). We aim to determine whether: 1) systemic expression of endogenous secretory RAGE (esRAGE) after the induction of diabetes can prevent the development of DN in mice with streptozotocin-induced diabetes; 2) the protective effects of esRAGE are attributable to interruption of signaling via the HMGB1receptors (TLR2, TLR4 and RAGE).

Correlation between CgA and TNF receptor-I (TNFR-I) and TNFR-II has been evaluated in patients before the initiation of treatment with Infliximab® and compared it with the value calculated this website during treatment [74]. The authors observed a high correlation between

CgA and both receptors. Moreover, they found that treatment with anti-TNF-α monoclonal antibodies (mAbs) abrogated the correlation between CgA and TNFR-I and TNFR-II, but it should be mentioned that in this study anti-TNF-α mAbs treatment did not modify the mean levels of CgA and TNFRs but led only to the abrogation of the correlation between CgA and TNFRs, implying that perhaps other indirect factors are associated in this effect. Three years later, the same group described that patients with RA have significantly higher serum levels of CgA

and TNFRs compared with controls and that the highest levels of CgA identify the population of patients with extra-articular manifestations [74]. Taken together, these results suggest that CgA might be involved in the pathogenesis of inflammatory autoimmune disease through a complex interaction with TNF-α, mediated by as yet-undefined factors. In a series of papers Metz-Boutigue’s group, who have published extensively on granins, showed a link between serum concentration of CgA and outcome in patients admitted with or without systemic PI3K Inhibitor Library inflammatory response syndrome. CgA concentrations were correlated positively with inflammation markers such as procalcitonin and C-reactive protein, but also with simplified acute physiological score (SAPS). A Cox PTK6 model confirmed that CgA and SAPS were independent predictors of outcome [75,76]. In addition, a significant association has been reported between CgA level and periodontitis, again

showing a close relationship between the level of CgA and the inflammatory process [77]. The hypothesis that Cgs-derived peptides are involved in mechanisms modulating altered colonic motility and visceral pain induced by gut inflammation was tested for the first time in 2004 using an application of acetic acid (AA) in vitro and in vivo. Using the writhing test, a model of somato-visceral pain, we have demonstrated that depending upon the Cgs-derived peptides used (bCgA 4–16, 47–66), they could display pro- and anti-nocicpetive effects [78,79]. In the context of smooth muscle contraction, Cgs-derived peptides modulate the effect of AA on human and rat smooth muscle contraction via a direct action on the calcium L-type channel or towards an indirect action through the enteric nervous system (motorneurone and type-C sensitive fibre) [80,81]. All these data provide proof of concept that Cgs and Cgs-derived peptides seem to play an important role in the development of inflammatory pathologies, and different groups have now focused their attention upon characterizing a mechanistic explanation. The studies discussed in this review provide evidence in favour of a key role of gut hormones in intestinal inflammation.