We hypothesized that RIG-I signaling drives the HLA-I antigen presentation machinery during hantavirus infection. Indeed, A549 cells pretreated with BX795, a potent inhibitor of TANK-binding kinase 1 (TBK1) and IκB kinase-epsilon (IKKε) [27], did not increase HLA-I expression in response to HTNV (Fig. 8). BX795 interferes with RIG-I as well as Daporinad manufacturer TRIF-dependent signaling. To analyze the requirement of innate signaling for HLA-I upregulation in more

detail, A549 cells with stable gene knockdowns (KDs) were generated by transfection of plasmids expressing specific small hairpin RNA (shRNA). HTNV-induced HLA-I upregulation was totally abrogated in RIG-I KD A549 cells as compared to parental A549 cells or A549 cells expressing nontarget selleck kinase inhibitor shRNA (Fig. 9A and B), although HTNV replication was clearly increased

(Fig. 9C). In contrast, KD of the double-stranded RNA-activated protein kinase (PKR) [28] did not significantly affect HLA-I surface expression in response to HTNV (Fig. 9A and B) or viral replication (Fig. 9C). Similarly, MyD88-dependent TLR signaling pathways were not important as KD A549 cells increased HLA-I surface expression after HTNV infection (Fig. 9A and B). Intriguingly, A549 cells with stable KD of TRIF completely failed to upregulate HLA-I surface expression upon HTNV infection similar to RIG-I KD A549 cells (Fig. 9A and B). In sum, HTNV-driven HLA-I upregulation requires both RIG-I and a TRIF-dependent viral sensor such as TLR3. In this study, we searched for mechanisms underlying the vigorous responses of HLA-I-restricted T cells in hantavirus-infected patients.

HTNV-induced HLA-I surface expression required live virus and was observed on both actively infected and bystander cells. Our experiments with reporter constructs transfected into A549 cells revealed that HTNV transactivates the promoter elements of all genes encoding classical human HLA-I molecules (HLA-A, -B, -C), which present antigen-derived epitopes to CD8+ T cells. In contrast, regulatory Vitamin B12 elements in the promoter region of genes encoding nonclassical HLA-I proteins did not significantly respond to HTNV infection. Virus-induced upregulation of classical HLA-I molecules in HTNV-infected humans may further increase the frequency of activated T cells, which has been positively correlated with disease severity [10]. It is unclear at the moment which HTNV-induced transcription factors actually bind to the various regulatory elements and cause these locus-specific differences. HLA-I upregulation on HTNV-infected A549 cells was blocked by pretreatment with epoximicin. This suggests that proteasome-independent mechanisms such as increased stability of HLA-I complexes on the cell surface are not involved. Transcriptional enhancement of HLA-I expression requires concomitant upregulation of TAP components to match the increased demand for HLA-I-binding peptides in the ER.

This implies that 2B4–CD48 interaction might be involved actively in SLE. Furthermore, our study using 2B4-deficient mice showed that 2B4–CD48 interactions play a regulatory role in generating gender-specific immune MG132 responses. This gender-specific immune response was mediated by NK cells [34]. Thus, one could speculate that reduced expression of 2B4 on NK cells from SLE patients may be involved in the gender bias seen in SLE. Analysis of expression of CS1 isoforms indicates differential expression

of CS1-L and CS1-S isoform in SLE PBMCs, reminiscent of Ly108 expression in lupus-prone mice [59,60]. The CS1-S isoform does not contain two ITSMs and does not mediate signalling [38]. Healthy individuals express three- to sevenfold higher levels of CS1-L over CS1-S. In SLE

patients this expression ratio is altered, affecting signalling via CS1. We have also found that healthy individuals expressed five- to eightfold higher levels of h2B4-A than h2B4-B. However, some patients with SLE showed increased expression of h2B4-B, while some patients with SLE showed more predominance of h2B4-A over h2B4-B than in healthy controls. The structural difference between 2B4 and A and 2B4-B is found in the ligand binding region of the extracellular domain, and our recent study showed that h2B4-A and h2B4-B activate NK cells differentially upon CD48 interaction [23]. At present the ligand for h2B4-B is not known. If h2B4-B interacts

with an unidentified ligand, altered expression of h2B4-B in SLE may impact immune signalling in SLE. Further https://www.selleckchem.com/products/icg-001.html studies on the functional consequences of altered expression of SLAM family receptors will greatly improve our understanding of SLE pathogenesis. Fenbendazole This study was supported by UNT Health Science Center Seed grant G67704 and a grant from Texas Higher Education Coordinating Board (to P. A. M.). We would also like to thank the nursing staff at JPS Hospital and Patient Care Center, UNT Health Science Center, Fort Worth, Texas for co-ordination in conducting the study. The authors declare no conflict of interest. Fig. S1. CS1-high expressing B cells are plasma cells. Total peripheral blood mononuclear cells (PBMCs) from healthy individual (a) and systemic lupus erythematosus (SLE) patients with active disease (b) were first analysed by CD19 versus CS1. CS1-high B cells (blue dots), CS1-low B cells (red dots) and CS1-negative negative B cells (green dots) were gated and the surface expression of CD27 is shown in histogram. As seen in (b), CS1-high expressing B cells express high levels of CD27 (mean fluorescence intensity: 25), indicating that they are plasma cells. Please note: Wiley-Blackwell are not responsible for the content or functionality of any supporting materials supplied by the authors. Any queries (other than missing material) should be directed to the corresponding author for the article.

g. Andersson

et al., 1972) and will probably influence the immune responses observed in this study to some extent. However, there are several reports of lipopolysaccharide-free phage also causing immune stimulation due to the virus-like structure of the phage coat (Gorski et al., 2003; Miedzybrodzki et al., 2005) and CpG motifs in the phage DNA (Klinman, 2003) and it is possible that all three factors (lipopolysaccharide, CpG motifs and the repeating Vemurafenib order peptide motif of the phage coat) will contribute to the immune responses observed. Typically, using our current purification procedures, the dose given to rabbits in this trial would contain 500–2500 EU per dose – higher than currently allowed for human vaccines. However, none of the rabbits used in this study showed any signs of inflammation at the site of injection, or fever

or other distress throughout the course of the experiment. This agrees with earlier research, where phages have been given to animals by a variety of routes, with no reported adverse reactions caused (e.g. see Clark & March, 2004a). This lack of inflammatory response/fever suggests that the role of lipopolysaccharide selleck chemical in generating the responses observed in this trial may be relatively minor. The results presented here are preliminary, with further work needed to quantify and qualify immune responses in more detail. It should be noted, however, that the only correlate of protection measured to test whether immunity against hepatitis B has been achieved is a serum antibody responses against the small surface antigen (Yu et al., 2004; Plotkin, 2010); hence, the highly significantly PAK5 increased immune responses presented here do suggest that further trials with the phage vaccine are merited. Phage

vaccination against hepatitis B potentially has several advantages over the standard recombinant-protein-based vaccination. Because of their relatively straightforward production on a prokaryotic host, they should be relatively cheap to manufacture. Following administration with a phage vaccine, the intracellular synthesis of vaccine protein should ensure that post-translational modifications occur correctly and that the viral envelope most closely resembles that found in a natural infection. The phage particles themselves are relatively stable at a variety of temperatures and can be freeze-dried for storage and transport (Jepson & March, 2004). To expand on the results presented here, animal experiments are currently being planned to examine the effect of dose (phages given per dose and number of doses), as well as the route of administration. Here, we have shown that bacteriophage-mediated DNA vaccination gives rise to antibody levels in rabbits that are higher than those produced after vaccination with a commercially available recombinant protein vaccine, using one of the recommended delivery schedules.

3e). At all the doses tested, there was no significant difference in IL-2 production by T cells activated by SD-4+/+ versus SD-4−/− Selleckchem Tipifarnib DC. Altogether, SD-4 deletion had no impact on T-cell responses in the absence of accessory signals delivered by DC, but it augmented the DC-induced response (enhanced co-stimulatory signals resulting from lack of the inhibitory function

of DC-HIL/SD-4 between APC and T cells). Since SD-4−/− T cells were hyper-reactive to allo-antigen in the mixed lymphocyte reaction (Fig. 3a), we examined their effect on acute GVHD (Fig. 4). BALB/c mice were γ-irradiated at a sub-lethal dose and then infused with T-cell-depleted allogeneic BM cells (from C57BL/6 mice) with or without CD3+ T cells isolated from KO or WT mice. Body weight was noted weekly and survival was noted daily through to day 100. All mice lost about 30% of initial body weight within a week after BM transplantation,

but recovered some weight during the 2nd week. Thereafter, differentially treated mice displayed disparate https://www.selleckchem.com/products/XL184.html outcomes (Fig. 4a). Mice that received BM cells alone completely recovered their weight 3 weeks post-BM transplantation and survived for at least 100 days. Mice that received BM cells plus SD-4+/+ T cells partially recovered their weight, with 50% dying by day 32, and the rest survived for at least 100 days (Fig. 4b). By contrast, mice that received BM cells plus SD-4−/− T cells lost weight progressively (up to 40%) due to severe diarrhoea, with 50% dying by day 14, and all dead by day 32. We also examined proliferation of infused T cells in recipients, by measuring the number of donor-derived T cells (H-2Kb+) in spleen and liver of mice at day 5 post-BM transplantation (Fig. 4c,d). In spleen (Fig. 4c), there was twofold to threefold greater CD4+ and CD8+ SD-4−/− T cells than SD-4+/+ T cells, and also more CD69+ (activated) cells than in recipients of SD-4+/+ T cells. Similar results were observed in liver, which is another major target of acute GVHD (Fig. 4d).[1] These results indicate that infusion of T cells devoid

of SD-4 worsens morbidity and mortality of acute GVHD, most likely through hyper-reactivity to allo-antigen. Because donor-derived Treg cells are known to play a pivotal Olopatadine role in preventing GVHD induced by co-injection of BM cells and T cells isolated from C57BL/6 mice into total body γ-irradiated BALB/c mice,[24] we studied the influence of SD-4 deletion on the T-cell-suppressive activity of Treg. We examined expression of SD-4 on conventional CD4+ Foxp3− T cells (Tconv) versus CD4+ Foxp3+ Treg cells (Fig. 5). The Tconv and Treg cells freshly isolated from naive WT mice represented 90% and 10%, respectively, and neither expressed SD-4. In contrast, PD-1 was expressed by a minuscule fraction of Tconv cells (4·6%) and by some Treg cells (22% of Foxp3+ cells) (Fig. 5a). The Tconv and Treg cells were activated by culture for 2 days with immobilized anti-CD3/CD28 antibody.

Notch signaling was found to be important for in vitro development of adult [[58]] and fetal CLPs [[20]] into RORγt+ ILCs. Interestingly,

https://www.selleckchem.com/products/ink128.html the latter study suggested a stage-specific requirement of Notch signaling in the development of RORγt+ ILCs as Notch signaling was required in an early stage of development of these cells but inhibited a subsequent step [[20]]. The relevant Notch for this role could be Notch2 [[58]] but this has yet to be confirmed in in vivo experiments. Rorγt+ cells in Ahr−/− mice express lower levels of the anti-apoptotic protein Bcl-2 and accordingly are more apoptotic [[54]]. Bcl-2 might be induced by the major cytokine receptors expressed on Rorγt+ ILCs, namely IL-7Rα and ckit; check details however, there are conflicting data with regard to the link of AhR and IL-7Rα. In one study, expression of IL-7Rα was decreased by AhR ablation [[54]], whereas another group did not observe any change in IL-7Rα expression on Ahr−/– ILCs

[[55]]. cKit, which is the receptor for stem cell growth factor, may be a direct downstream target of AhR since expression of this receptor is strongly decreased in Ahr−/− ILCs [[55]]. It is possible that the Rorγt+ ILC numbers are regulated by AhR in a cKit dependent manner. This suggestion comes from observations made in KitWv/Wv mice, which express a ckit variant with impaired kinase

activity. These mice not only show diminished numbers of Rorγt+ ILCs, but also reduced numbers and sizes of CPs and ILFs. These findings strongly suggest that AhR regulates maintenance of RORγt-dependent ILCs by controlling ckit expression. As in Th17 cells, AhR also appears to be required for optimal IL-22 production 4��8C by the ILC22 population. The reduction of Rorγt+ ILC numbers in the gut, and the decreased capacity of these cells to produce IL-22, has functional consequences because AhR-deficient mice succumb to infection with C. rodentium and hydrodynamic injection of an IL-22-expressing plasmid into the tail vein reestablishes protection against C. rodentium [[54]]. In this setting, IL-23, produced by activated macrophages and DCs, controls IL-22 production by ILCs. Interestingly, AhR-deficient mice display reduced IL-23 receptor expression and IL-23 responsiveness [[52]]. It is likely that AhR directly controls IL-22 expression, as the Il22 locus contains multiple AhR-responsive elements [[54]]. Interestingly these elements are clustered with Ror-responsive elements and, in the Il22 locus, both Rorγt and AhR bind directly to their response elements. Whereas AhR recruitment to the well-known AhR target Cyp1a1 is unaffected by Rorγt, AhR binding to the Il22 locus is strongly enhanced by Rorγt [[54]].

Acute kidney injury (AKI) was defined as ≥0.3 mg/dL increase in creatinine levels from baseline within 48 hours according to KDIGO guidelines. Results: C2 (1.46 ± 0.1 mg/dL) and C3 (1.53 ± 0.12 mg/dL) levels were significantly higher from baseline Cr (1.15 ± 0.6 mg/dL) values. AKI was observed in 36 patients (41.37%) on the third day of iloprost infusion. Binary logistic regression analysis Volasertib price of comorbidities and drugs revealed that smoking and no ASA use were the primary predictors (p: 0.02 and p:0.008

respectively) of acute kidney injury during iloprost treatment. In the third day of the infusion urinary output of patients was significantly increased from the initiation of therapy (1813.30 ± 1123.46 cc vs. 1545.17 ± 873.00 cc). 74.14 ± 9.42 mm Hg vs. 70.07 ± 15.50 mm Hg The renal function improved after the second week of the treatment. Conclusion: Even though the iloprost treatment is effective in peripheral arterial disease patients who are not suitable for surgery, severe systemic vasodilatation might cause renal ischemia

ending up with non-oliguric acute kidney injury. Smoking, no ASA use and lower diastolic BP are the clinical risk factors for AKI during iloprost treatment. WU PEI-CHEN1, WU VIN-CENT2 1Da Chien General Hospital; 2National Taiwan University Hospital AP24534 Introduction: There are few reports on temporary dialysis-requiring acute kidney injury (AKI) as a risk factor for future upper gastrointestinal

bleeding (UGIB). The aim of our study was to explore the long-term association between dialysis-requiring AKI and UGIB. Methods: We performed a propensity score-based case control study using the claim data of Taiwan’s National Health Insurance database for hospitalized patients aged ≥18 years who recovered from dialysis-requiring AKI between 1998 and 2008. We also identified long-term de novo UGIB and mortality using time-varying Cox proportional hazard models adjusted for subsequently developed chronic kidney disease (CKD) and end-stage renal disease (ESRD) after AKI. Results: A total of 4,565 AKI-recovery patients and the same number of matched non-AKI patients were analyzed. After a median follow-up time of 2.3 years, the incidence rates of UGIB were 69 (by lenient criterion) and 50 (by stringent criterion) Thymidine kinase per 1,000 patient-years in the AKI-recovery group and 48 (by lenient criterion) and 31 (by stringent criterion) per 1,000 patient-years in non-AKI group (both p < 0.001). Figure 1 shows the Kaplan-Meier curve for long-term UGIB-free probability depicting separately for the AKI-recovery and the non-AKI groups (Log-rank test p < 0.001). When compared with patients in the non-AKI group, the multivariate hazard ratio (HR) for UGIB was 1.43 for dialysis-requiring AKI, 1.88 for time-varying CKD, and 2.30 for ESRD (all p < 0.001). Finally, the risk for long-term mortality increased after UGIB (HR 1.

Structurally, the purpose of the placenta in mammals is to bring maternal and fetal circulatory systems in close proximity to facilitate exchange of nutrients, oxygen, waste, and other factors.[2] Several good reviews of comparative placentation exist.[3-7] Placentae are usually described by the layers existing between fetal trophoblast, which itself envelops fetal vessels and mesenchymal

cells, and maternal blood.[2] The controversy of placentation and the validity of animal models will likely continue because while it is assumed that differences in placentation will lead to different adaptive mechanisms, experimental changing of placentation in certain animals is likely extremely challenging. The human placenta is said to be hemochorial,[2] in that maternal blood is in direct contact with selleck fetal trophoblast. There are, however, other points of contact between click here maternal and fetal tissues, for example in the villous structures that anchor the placenta.[8] The human placenta moreover is said to be interstitial, in that implantation occurs completely within the maternal uterine wall[4] thus allowing for multiple points of interaction between maternal and fetal tissues early in gestation. Primates commonly used in research, for example baboons, macaque, chimpanzee, also have hemochorial placentas[3,

6] with more or less invasion upon implantation, and a villous organization, although this is not true for all primates (e.g. lemurs[3]). The vascular structure of human placenta undergoes a revision in early gestation in which trophoblast lines maternal uterine arteries[9] to allow for maximal blood flow.[10] The placenta in rats (see recent review by Soares et al.[11]) mice, and guinea pigs (rodents) is similar to that in humans

in that maternal blood is in direct contact with trophoblast. There are subtle(?) structural differences between human and rodent placentae, including the flow of blood due to a labyrinthine as opposed to a villous organization, the depth of trophoblast invasion,[6] and the trophoblast subpopulations.[2] For example, an additional layer of trophoblast, the giant cell layer, in addition to cytotrophoblast and syncytital Endonuclease trophoblast has led some authors to call the rodent placenta ‘hemotrichorial’. Because of only one trophoblast layer, the guinea pig placenta is sometimes referred to as ‘hemomonochorial’. In addition to structural differences, there are subtle differences in the expression of proteins, such as those involved in immune regulation.[12-15] While the definitive placenta is in place for a short time relative to gestation in mice and rats,[2] the longer gestation in guinea pigs makes this less true. Rabbits belong to the group of mammals called lagomorphs. Their placentas are hemochorial with two trophoblast layers, a syncytium layer and a cytotrophoblast layer, which is similar to humans, but organized in a labyrinthine structure.

Though the tissue remained culture negative after 6 weeks, PCR again confirmed the presence of MH. He recommenced antibiotic therapy of clindamycin, ciprofloxacin and rifampicin without dapsone selleck monoclonal humanized antibody and improvement in arthralgia was noted at review 2 weeks later. It

is anticipated that he will need life-long antibiotic suppression. This case highlights the difficult diagnostic and therapeutic implications of atypical infections in transplant patients. MH infections have been described in renal, heart, liver and bone marrow transplant recipients.[3] We believe this is the first reported case of MH presenting atypically with intra-nasal lesions and subsequent disease relapse at a new anatomical site with skin and presumably synovial involvement. Clinical features of MH in this population are wide-ranging, with reported pyomyositis with abscesses, tenosynovitis, septic arthritis, osteomyelitis, pneumonitis, septicaemia and skin lesions varying from nodules, papules, cysts to tender discharging ulcers.[3, 4] It is likely that cell-mediated immunity plays a significant role in

the clinical evolution of the disease and outcome, with low levels of absolute CD4 count associated with worse outcomes including disseminated disease and death.[3] The presence of MH metastatic infection raises the possibility of over-immunosuppression Erlotinib mw in this patient. The occurrence of early rejection meant a reduction in immunosuppression was approached cautiously. Although culture remains the gold standard for diagnosis, MH is notoriously fastidious and slow growing requiring temperatures of 30–32°C and does not culture on routine Mycobacterium media. Given the difficulty of detection of this organism it is likely that this infection has been under recognised and under reported in the literature.

Diagnosis for optimal detection of MH includes acid fast staining, culturing at two temperatures with iron-supplemented media and molecular L-gulonolactone oxidase detection using PCR.[2] Treatment with multiple active agents was commenced based on a small series which found 100% of sixteen MH isolates were sensitive to ciprofloxacin and clarithromycin and 94% rifampicin sensitive. Treatment with at least two agents is recommended, as resistance has been described using clarithromycin, azithromycin, rifampicin and amikacin in NTM infections.[3, 5] Further complicating the management in transplant recipients is the interaction of immunosuppressive agents, particularly tacrolimus and cyclosporine and rifamycins such as rifampicin. The dose of calcineurin inhibitors often needs to be increased three to five fold with close monitoring of drug levels due to the induction of enzyme cytochrome P450. Transplant patients treated with rifampicin based regimens for Mycobacterium tuberculosis have been associated with an increased risk of allograft rejection and loss.[6] There is currently no consensus with respect to duration of therapy.

Activated DCs present antigens normally not presented via MHC molecules under non-inflammatory conditions, e.g. in the absence of infection. This might notably be the case for self-antigens released in the inflammatory milieu physiologically or upon immune-mediated tissue damage. A possible candidate in this regard is HSP60, which can enhance the function of CD4+CD25+ Tregs directly 22, but whose immunodominant peptide p277 bears tolerogenic properties in T1D, such that it is now evaluated in clinical studies to treat this disease 47, 48. As discussed above, endogenous molecules like HSP60 may thus be released during viral infection and confer CD4+CD25+ Treg enhancement directly

via TLR2, but also indirectly via antigenic presentation by DCs. In addition, presentation of other self-antigens AP24534 purchase by DCs under inflammatory conditions might promote the recruitment of AZD5363 supplier diabetogenic CD8+ T cells in the vicinity of DCs and their subsequent impairment by these cells. Such a phenomenon could occur for example through the PD-L1/programmed death-1 pathway, as suggested by our previous study 12. In this regard, our present results and data not shown indicate that lymphoid cells stimulated through TLR2 in vitro or in vivo acquire high PD-L1 expression. In sum, it is possible that the contribution

of DCs in TLR2-mediated prevention of T1D is to promote Treg function while curbing autoreactive responses. A promising alternative to the therapeutic induction or enhancement of Tregs in vivo to treat

T1D is their expansion in vitro for cell-based therapy. Our results suggest that stimulation via TLR2 might be well-suited for this purpose. Strategies exist to grow human CD4+CD25+ Tregs in large numbers in culture 49, and effort is currently undertaken to develop this approach in clinical trials 50. A number of strategies consist of expanding Tregs polyclonally through stimulation via the TCR, along with co-stimulation (e.g. anti-CD3 and anti-CD28). While such expanded Tregs exhibit good preventive capacity in autoimmune diabetes, they seem to show rather limited efficacy in the reversion (as opposed to prevention) of new-onset disease. This may be due in part to their non-antigen-specific nature, but also notably to the inability of TCR-restricted Terminal deoxynucleotidyl transferase stimulation to augment their suppressive function. Our results indicate that stimulation through TLR2 could be used as a means to not only increase the number of CD4+CD25+ Tregs in vitro, but also ameliorate their in vivo tolerogenic property in T1D. We identify here a mechanism by which innate immunity, namely TLR2 stimulation, promotes immunoregulation and controls autoimmune processes in T1D. Therefore, it appears that similar phenomena account for both development and prevention of autoimmune diabetes. This suggests that the recurring occurrence of infectious events during early life might promote autoimmunity but will also drive the immune system to build increased immunoregulatory force.

If the products of these cells are toxic to developing larvae (L3 and L4 stages) of hookworms, this may explain why acquired immune responses are particularly effective against invasive stages, compared with adult worms. Finally,

Regorafenib supplier the experiment described in this paper, has made novel contributions to our understanding of the events that occur in the mucosa during both primary and secondary infections with the hookworm, A. ceylanicum in the hamster model. This model is being exploited in the quest to develop a protective vaccine for hookworms and the current data will help to inform those studies, particularly when evaluating the outcome of vaccine trials in the hamster model (35–37). The results reported here raise interesting questions about the role of Paneth cells, and about how Th2-driven intestinal inflammatory responses are controlled by cytokines and regulated by the parasites, VX-809 given the contrasting dynamics of the initial appearance of the different cellular compartments and of their return to baseline levels once the worms have been removed. We thank the Ministry of High Education of the Kingdom of Saudi Arabia for the provision of a postgraduate studentship

for LMMA. We are also grateful to Dr. Catherine Lawrence and Prof. P. Garside for training provided for LMMA in the initial stages of this project. “
“Recently, Sirtuin 1 (SIRT1) has been implicated in the molecular control of ageing and immune response. Although the remodelling of periodontal ligament (PDL) in response to mechanical stress (MS) is mediated by several host factors, including cytokines and chemokines, the transmission of mechanical stimuli into specific cellular activity is still not understood fully. This study aimed to investigate the effects of MS, particularly cyclic strain, on immune response genes, as well as SIRT1 and its signal transduction pathways, in human PDL cells. MS up-regulated the expression OSBPL9 of SIRT1 and immune response genes encoding cytokines [tumour necrosis factor

(TNF)-α, interleukin (IL)-1β], chemokines [IL-8, monocyte cheoattractant protein (CCL)-20], defensins [human β-defensin (hBD)-2, hBD-3] and Toll-like receptors (TLR-2 and TLR-4) in a force- and time-dependent manner. The SIRT1 inducers resveratrol and isonicotinamide attenuated MS-induced cytokine and chemokine expression, but enhanced the expression of defensins and TLRs. Blockade of SIRT1 activity by the SIRT1 inhibitors sirtinol and nicotinamide and down-regulation of SIRT1 expression by SIRT1 siRNA reduced the stimulatory effects of MS on defensins and TLRs, but increased its effects on cytokines and chemokines. MS induced activation of protein kinase B (Akt), protein kinase C (PKC), nuclear factor (NF)-κB and p38 mitogen-activated protein kinase (MAPK), c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK).