In tissues, inflammatory signals mediated by direct recognition of fungal cell wall components or other fungal products by PRRs, recruit additional immune cells and drive adaptive immune responses. IFN-γ produced by Th1 lymphocytes is fundamental for stimulating the antifungal activity of neutrophils. The central role of endogenous IFN-γ in the resistance against

systemic fungal infection is underscored by the observation that KO mice deficient in IFN-γ are highly susceptible to disseminated C. albicans infection [36]. In addition, mice deficient in IL-18, which plays a crucial role in the induction of IFN-γ, are also more susceptible to disseminated candidiasis MG-132 order [37]. Th1 also appears to be protective in the host defense against Aspergillus. Cells producing IFN-γ are induced by Aspergillus in immunocompetent mice. Live conidia, which undergo swelling and germination, are able to prime Th1 responses [38]. It has been elegantly demonstrated that CD4+ T cells differentiate during respiratory fungal infection, with TLR-mediated signals in the lymph node enhancing the potential for IFN-γ production, whereas other signals promote Th1 differentiation Selumetinib in the

lung [39]. Although many studies focused on the pathological aspects of IL-17-producing T cells in many autoimmune diseases, studies examining T-cell polarization in response to PAMPs have identified an array of fungal components that preferentially induce the Th17 lineage [40], suggesting a role for Th17 cells in fungus-induced host defense, such as those specific for C. albicans, Pneumocystis carinii, and Criptococcus spp. The observation that mice deficient in IL-17RA show an increased susceptibility to disseminated C. albicans infection first demonstrated the critical involvement

of Th17 responses in protective anti-Candida host defenses [41]. Although this suggests a protective role for Th17 response in fungal infection, negative effects of Th17-mediated inflammatory responses to intragastric Doxorubicin in vitro C. albicans infection in mice have also been reported [42], as well as higher susceptibility to Candida and Aspergillus infection in absence of Toll IL1R8 (TIR8), a negative regulator of Th17 responses [43]. On the other hand, patients with impaired Candida-specific Th17 responses, such as patients with chronic mucocutaneous candidiasis, are especially susceptible to mucosal C. albicans infections [44]. These observations strongly indicate that Th17 responses are important for human anti-Candida mucosal host defense since patients with genetic defects in the receptor dectin-1 or in its signaling (a potent activator of Th17) suffer from chronic mucosal fungal infections [45, 46]. Mucosal Th17-cell subsets and their associated cytokines, IL-17A, IL-17F, and IL-22, have been shown to play key roles in discriminating colonization and invasive fungal disease [47-49].

71.54 In studies of adult intensive care patients, plasma NGAL concentrations on admission constituted a very good to outstanding biomarker for development of AKI within the next 2 days, with AUC-ROC ranges of 0.78–0.92.55,57 In subjects undergoing liver transplantation, a single plasma NGAL level obtained within 2 h of reperfusion was highly predictive of subsequent AKI, with an AUC-ROC of 0.79.58 Finally, in a study of adults in the emergency department setting, a single measurement of urine NGAL at the time of initial presentation predicted AKI with an outstanding AUC-ROC of 0.95, and reliably distinguished pre-renal azotemia from intrinsic AKI and

from CKD.59 Thus, NGAL Erlotinib is a useful early AKI marker that predicts development of AKI even in heterogeneous groups of patients with multiple comorbidities and with unknown timing of kidney injury. However, it should be noted that patients with septic AKI display the highest concentrations of both plasma and urine NGAL when compared with those with non-septic AKI,56 a confounding factor that may add to the heterogeneity of the results in the critical care setting. The variable performance of biomarkers such as NGAL in the critical care setting may also be attributable to the fact that this patient population is extremely heterogeneous,

and the aetiology and timing of AKI is often unclear. A high proportion of patients may have already sustained AKI on admission to the ICU. Although sepsis accounts for 30–50% of all AKI encountered in critically ill patients, other aetiologies include exposure to nephrotoxins, selleck kinase inhibitor hypotension, kidney ischaemia,

mechanical ventilation and multi-organ disease. Each of these aetiologies is associated with distinct mechanisms of injury that are likely to be active at different times with different intensities and may act synergistically. Despite the myriad confounding variables, a recent meta-analysis revealed an overall for AUC-ROC of 0.73 for prediction of AKI, when NGAL was measured within 6 h of clinical contact with critically ill subjects and AKI was defined as a >50% increase in serum creatinine.41 Because of its high predictive properties for AKI, NGAL is also emerging as an early biomarker in interventional trials. For example, a reduction in urine NGAL has been employed as an outcome variable in clinical trials demonstrating the improved efficacy of a modern hydroxyethylstarch preparation over albumin or gelatin in maintaining renal function in cardiac surgery patients.60–62 Similarly, the response of urine NGAL was attenuated in adult cardiac surgery patients who experienced a lower incidence of AKI after sodium bicarbonate therapy when compared with sodium chloride.63 In addition, urinary NGAL levels have been used to document the efficacy of a miniaturized cardiopulmonary bypass system in the preservation of kidney function when compared with standard cardiopulmonary bypass.

The ureter was ligated at approximately 1 cm below the renal hilum with 3-0 silk suture. The abdominal wound was closed, and rats were returned to the cages. Control rats underwent abdominal INK 128 nmr incision and approximation with no ligation of the ureter.19,20 Six rats of the two groups were killed at 14 days and 28 days after surgery, respectively, and their renal tissues were collected for histological and molecular biology determination. After

10% neutral formaldehyde fixation, the renal tissues were dehydrated through a graded ethanol series and embedded in paraffin. Sections were prepared on a microtome and stained with masson’s trichrome staining. Renal pathology was observed by light microscope, the severity of the renal lesion was presented by the RIF index. Blue granular or linear deposits were

interpreted as positive areas for collagen staining. Semi-quantitative evaluation was performed by computer-assisted image analysis (DMR + Q550, Leica Co., Germany). The area of positive staining for fibrosis was measured at 400-fold original magnification in 50 fields (ignoring the fields containing glomerular parts) and expressed as a percentage of the total area.21 The extent of interstitial fibrosis was scored as absent (0), involving less than 25% of the Akt inhibitor area (1), involving 26–50% of the area (2), and involving greater than 50% of the area (3).22 RIF index was obtained by the formula as follow: GSI = (0 × n0 + 1 × n1 + 2 × n2 + 3 × n3)/(n0 + n1 + n2 + n3) = (0 × n0 + 1 × n1 + 2 × n2 + 3 × n3)/50. All the fields were selected from coded sections for each rat at random and the scores obtained by two investigators were averaged. Cell apoptosis was examined by the TdT mediated dUTP nick end labelling (TUNEL) assay (Roche Inc., Basel, Switzerland) as described

previously.23,24 Six slides from each kidney were evaluated for percentage of apoptotic cells by using the TUNEL assay. Then 10 watch fields, which didn’t include the glomerular parts, were chosen at random under a microscope on each section. Brown staining 4��8C of cell nuclei was considered as apoptotic cells. Positive brown cells and total cells were counted. The formula for apoptosis index as the indicator of apoptosis was as follows:23 cell apoptosis index = positive cells/total cells × 100%. The scores obtained by two investigators were averaged. Renal tissue fixed with 4% buffered paraformaldehyde was embedded in paraffin, and 4 µm thick sections were stained. The positive area was measured quantitatively using a computer-aided manipulator (DMR + Q550, Leica Co., Germany). For immunohistochemical analysis of PHB, Caspase-3, TGF-β1, collagen-IV (Col-IV) and fibronectin (FN), the sections were deparaffinized, washed with phosphate-buffered saline (PBS), and treated with 3% H2O2 in methanol for 10 min.

[25, 26] Candida spp., especially C. albicans, are able to produce and secrete various hydrolytic enzymes, particularly proteinases, lipases and phospholipases.[21] Shimizu et al. [27] and Abu-Elteen et al. [28] demonstrated the relevance of proteinases, hyaluronidases, condroitinases and phospholipases as virulence–related factors, reporting that secretory strains of Candida spp. showed an increased ability to invade tissues compared to non-secretory strains. According to Costa et al. [29], the activity of

proteinases and phospholipases is directly related to the promotion and establishment of infection. According to studies by Noumi et al. [30], hydrolytic enzymes and adhesins produced by C. albicans present themselves as the largest factor selleck chemical associated with virulence, a fact previously suggested by Neugnot et al. [31]. Secreted aspartic proteinase (Sap) was first described in 1965 and was named Candida acid proteinase due to its optimal activity at acidic pH ranges and

because it was primarily found in yeast of the genus Candida.[32, 33] Sap may be considered CX-5461 cell line the most important hydrolytic enzyme among the virulence-associated factors of Candida spp.[34] Saps are believed to contribute to the adhesion and invasion of host tissues through the degradation or distortion of cell surface structures or the destruction of cells and molecules of the immune system, to avoid or resist microbicidal attack.[35, 36] Saps have a broad substrate specificity and are able to degrade a variety of human proteins such as albumin, haemoglobin, keratin, collagen, laminin, fibronectin, mucin and almost all immunoglobulins, including immunoglobulin A, which is resistant to the majority of bacterial proteinases.[37]

Basically, these enzymes are involved in the digestion of proteins by providing nitrogen to aid the survival of fungal cells.[38] At first glance, they appear to be acquiring nutrients; however, Saps may have developed other functions related to virulence such as degrading structural proteins why and proteins of the immune system.[20, 21] In C. albicans, the production of Sap is encoded by a family of 10 SAP genes that are grouped into six subgroups or subfamilies: SAP1-3, SAP4-6, SAP7, SAP8, SAP9 and SAP10.[39-41] Gene transcription generates isoenzymes, named due to conformational and structural similarities among them.[40, 41] Sap1–Sap3 share 67% genetic identity and Sap4–Sap6 share as much as 89% identity. Sap1–Sap3 and Sap4–Sap6 are closely clustered. Sap7 only shares 20–27% identity with the other Sap proteins and is externally positioned. Sap8 is related to the clusters formed by Sap1–Sap3 and Sap4–Sap6. Sap9 and Sap10 differ from the other Sap1–8 isoenzymes and constitute a distinct group (Fig. 1).[42-44] All members of the family of Sap proteins possess four cysteine residues and two conserved aspartate residues.

OVA recipients (Fig. 4C). The absence of IFN-γ production by OT-II T cells in 11c.OVA was not due to immune deviation to Th2 as no significant click here IL-4 production was induced from OT-II recovered from either 11c.OVA or nontransgenic controls recipients (Fig. 4C). No IL-10 or TGF-β production was detected in cultures established from OVA-challenged 11c.OVA or nontransgenic recipients (data

not shown). Analysis of Foxp3 expression, which might indicate Treg development, showed a slight enrichment for Foxp3-expressing cells in OT-II T cells recovered from spleens of 11c.OVA (0.45±0.15% of OT-II, mean±SEM) relative to nontransgenic (0.03±0.03%, p<0.05) recipients, but this was present in only a low proportion of cells. Thus, no evidence was found that

conversion to Treg contributed substantially to inactivation of OT-II responses. On the whole, these data indicate that in nontransgenic recipients, memory T-cell responses established by transfer of OT-II T cells were preserved, whereas in 11c.OVA recipients, memory T-cell responses were terminated through mechanisms consistent with deletion and induction of unresponsiveness. Priming and differentiation buy Navitoclax of effector and memory T-cell populations occurs during the prodromal phase of autoimmune and inflammatory responses, before tissue damage and overt symptoms are fully developed and onset of the disease is detected. For this reason, therapies selleck kinase inhibitor developed with the goal of terminating established autoimmune or inflammatory

responses will require an effective approach to silencing effector and memory T cells. Here, we demonstrate that transgenic expression of cognate antigen by steady-state DC terminates memory CD4+ T-cell responses. It has long been thought that memory T cells are resistant to tolerance induction, therefore representing a substantial impediment to therapy of established autoimmune or inflammatory diseases. Indeed, heterologous immunity is a hurdle for induction of transplantation tolerance 19 although, countering this, we have recently demonstrated that memory CD8+ T-cell responses can be terminated if cognate antigen expression is targeted to DC 4. Susceptibility of memory and effector CD4+ T cells to peripheral tolerance induction and the possible mechanisms involved is less clear. Conflicting reports indicate that under some circumstances memory CD4+ T cells are resistant to tolerance induction 20, 21, whereas under others, effector CD4+ T cells appear susceptible 22, 23. In contrast to this, in vitro observations indicate that memory or post-activated CD4+ T cells are more sensitive than naïve CD4+ T cells to anergy induction in vitro by fixed APC or agents such as ionomycin and anti-CD3 mAb 24–26. We now demonstrate that CD4+ effector/memory T-cell responses can be also terminated by cognate antigen-expressing DC.

The current study suggests the possibility to manipulate NKT-cell activity in inflammatory disorders through intervention to the adenosine-A2AR pathway. “
“Human respiratory syncytial virus (hRSV) is the leading cause of respiratory illness in infants and young children around the globe. This pathogen, which was discovered in 1956, continues to cause a huge number of hospitalizations due to respiratory disease and it is considered a health and economic burden worldwide, especially in developing countries. The immune response elicited by hRSV infection leads to lung

and systemic inflammation, which results in lung damage but is not efficient at preventing viral replication. AG-014699 ic50 Indeed, natural hRSV infection induces a poor immune memory that allows recurrent infections. Here, we review the most recent knowledge about the lifecycle of hRSV, the immune response elicited PF-02341066 price by this virus and the subsequent pathology induced in response to infection in the airways. Novel findings about the alterations that this virus causes in the central nervous system and potential therapies

and vaccines designed to treat or prevent hRSV infection are discussed. In 1956 Morris and co-workers isolated a cytopathogenic agent from a colony of chimpanzees at the Walter Reed Army Institute of Research, which presented a respiratory illness characterized by coughing, sneezing and mucopurulent nasal discharge.[1, 2] The infected animals showed inflammatory damage in the upper respiratory tract and this condition was rapidly spread to other members of the colony, suggesting the presence of a highly infectious pathogen.[1] Because the major sign of disease in the affected monkeys was coryza – or nasal inflammation – the pathogen was termed ‘chimpanzee coryza agent’. One

year later, Chanock and Finberg[3] reported the isolation of a similar agent from two throat swab samples of infants with severe respiratory illness. These viruses were identical to the ‘chimpanzee coryza agent’ reported by Morris, suggesting that this pathogen Isoconazole could infect both chimpanzees and humans.[3] The unusual cytopathic effect caused by the virus on HEp-2 cells, characterized by the syncytia formation and giant cells in cultures, led to its current denomination as human respiratory syncytial virus (hRSV).[1] Human RSV is now the most important cause of acute lower respiratory tract infections (ALRTI) that include acute bronchitis, bronchiolitis, pneumonia and tracheitis in infants and young children worldwide.[4] Data from a recent meta-analysis showed that this pathogen causes up to 33·8 million ALRTI in children under 5 years of age each year, of which around 3·4 million of cases need hospital admission worldwide.[5] Further, hRSV infection causes the deaths of 66 000–199 000 children every year in developing countries.[5] For these reasons, hRSV is considered a global health burden.

151 However, investigators have shown that no interaction occurs when the itraconazole capsule is co-administered with the non-buffered enteric-coated ddI formulation that is currently marketed.152 Early studies of antacid co-administration

with posaconazole tablets suggested that elevations in gastric pH did not produce clinically significant changes in EGFR tumor posaconazole concentrations or exposure.153 However, a well-designed study using the currently marketed formulation and a proton pump inhibitor clearly demonstrates that posaconazole absorption is significantly impacted by changes in pH and food.45 Co-administration with a proton pump inhibitor reduces posaconazole Cmax and exposure Selumetinib nmr by 46% and 32% respectively.45 Food, irrespective of whether it is a solid or liquid and regardless of fat content, significantly increases the bioavailability of posaconazole.46,47,153 Indeed, the effect of food on posaconazole

pharmacokinetics is much greater than that of pH.45,153 Increases in gastric emptying caused by prokinetic agents such as metoclopramide may result in reductions in Cmax and exposure that are likely not clinically significant.45 In contrast, the co-administration of this azole with loperamide, an antikinetic agent, produces no clinically relevant effects on posaconazole pharmacokinetics.45 In patients who require acid suppression therapy and treatment with either itraconazole or posaconazole, the interactions can be managed. In patients requiring itraconazole therapy, the solution should be employed. For protracted courses of therapy, the solution may be impractical and an appropriate alternative antifungal agent should be considered. To maximise posaconazole absorption in patients requiring acid suppression therapy, the drug should be administered in divided doses with or after a high-fat meal, or at least with any meal, a nutritional supplement, or an acidic beverage.45 Induction of antifungal biotransformation.  Antifungal agents can produce additive toxicities with other

medicines and alter the distribution, metabolism and elimination of many other drugs. However, few drugs can enhance the toxicity, or decrease the Metalloexopeptidase serum concentrations or systemic exposure of antifungal agents. Medicines that affect the disposition of antifungal agents do so by inducing enzymes involved in oxidative or conjugative metabolism, or transport proteins. Interactions affecting the disposition of antifungal agents typically involve phenytoin, phenobarbital, carbamazepine, rifampin, ritonavir, efavirenz and other well-known inducers of CYP3A4. In addition, as illustrated by the interaction between rifampin and caspofungin, our understanding of the induction of transport proteins will grow as their role in drug disposition continues to evolve. The majority of interactions affecting the disposition of antifungal agents involves the induction of CYP3A4.

Representative plots showed that healthy individual and bladder carcinoma patients had similar Th17 numbers in the PBMCs (Fig. 1a). As shown in Fig. 1b, the mean frequency of peripheral blood Th17 cells in bladder carcinoma patients was comparable with that in healthy individuals (1·2 ± 0·7% versus 1·3 ± 0·6%). The population of Th17 cells in the TILs isolated from resected tumour specimens of patients with bladder carcinoma (n = 20) was also evaluated. Strikingly, as representative data showed, the percentage of Th17 cells in the TILs was higher than that in the PBMCs in the same patient (Fig. 1a and c). The mean percentage of Th17 cells in the CD4+ population was significantly

higher in TILs (8·2 ± 4·6%) compared with that in the PBMCs from bladder carcinoma patients (1·2 ± 0·7%, P < 0·01, Fig. 1b) or healthy individuals (1·3 ± 0·6%, P < 0·01, Fig. 1b). In some patients up Obeticholic Acid to 11% of the CD4+ TILs secreted IL-17 upon brief stimulation, suggesting that IL-17+ T cells may be differentiated predominantly in the tumour microenvironment. To characterize more effectively the CD4+ T cell population producing IL-17 ex

vivo, we also analysed their phenotype and cytokine profile in the tumour microenvironment. Our data showed that the CCR6 surface expression on Th17 cells in TILs was similar to that in PBMCs from patients or healthy controls (Fig. 2a), whereas CCR4 expression on Th17 cells in TILs was significantly higher than Digestive enzyme that in PBMCs from patients

or healthy controls (Fig. 2a). Our results showed that most of the tumour-infiltrating IL-17+ T cells expressed high levels find more of homing molecules, which might be involved in regulating lymphocyte migration. We further analysed the cytokine profile of human Th17 cells in TILs and PBMCs. Representative plots showed that Th17 cells in PBMCs from a healthy individual and a bladder carcinoma patient had similar lower levels of polyfunctional effector cytokines, including TNF-α and IFN-γ (Fig. 2b). In contrast, Th17 cells in TILs expressed high levels of TNF-α and IFN-γ. Almost half of the tissue Th17 cells were able to produce TNF-α or IFN-γ (Fig. 2c), which implied the possible existence of a developmental and/or functional relationship between Th17 and Th1 cells in bladder tumours. Treg were identified as CD4+CD25high T cells by selecting those CD4+ cells whose CD25 expression exceeded the level of CD25 positivity seen on the CD4 negative population [24] (Fig. 3a). The phenotypic characteristics of CD4+CD25–, CD4+CD25int and CD4+CD25high subsets from cancer patients and healthy donors were then analysed further by flow cytometry. The highest percentage of CD45RO+CTLA-4+ was detected in the CD4+CD25high subsets and the percentage, respectively, was 92% ± 2·5% (range: 89–94%) and 94% ± 3·6% (range: 85–99%), but CD127 and CD69 were not expressed in the CD4+CD25high subsets (Fig. 3b).

We speculate that one highly effective mechanism through which Treg cells limit neutrophil responses

is to reduce chemokine production perhaps by a variety of cells, including epithelial cells, macrophages (CXCL1 and CXCL2) and neutrophils (CXCL1). This finding expands upon previous observations showing that anergic regulatory T cells inhibit tissue invasion by T cells and granulocytes through chemokine metabolism.28 Similarly, Sarween et al.29 reported that CD4+ CD25+ Treg cells prevent tissue invasion by other T cells through effects on chemokine receptor and chemokine expression. The impact of Treg cells on inflammatory responses is not confined to B16FasL. Enhanced rejection of B16 cells observed after partial depletion of Treg cells is dependent X-396 concentration on innate immune responses Nivolumab in vitro and B16 tumours grow more rapidly in RAG−/− mice receiving CD4+ CD25+ cells compared with those receiving CD4+ CD25− cells. Full characterization of the early events following tumour cell inoculation in these mice is not possible because the inflammatory response, although biologically relevant, cannot be readily detected by immunohistochemistry. Hence, the B16FasL cell line serves a useful purpose as enhanced immunogenicity facilitates characterization of early events occurring after tumour cell inoculation. Other studies support a role for Treg cells in controlling neutrophil responses. Previous studies

of Helicobacter hepaticus-driven inflammatory responses in the gut indicated that adoptive transfer of Treg cells reduced neutrophil numbers in the spleen and lamina propria of chronically infected RAG−/− mice.30 There are many mechanisms involved in controlling immune responses in the skin. The ability of Treg cells to control the activity of CD8+ T-cell responses in the skin has been previously demonstrated.31,32 Our results show that Treg cells also control innate responses in the skin. These Treg cells may be activated by tissue damage or stimuli from melanoma cells and thereafter act

rapidly in an antigen non-specific fashion, to be able to control early innate immune activation. We found no detectable increase Cediranib (AZD2171) in the level of skin Treg cells after inoculation of tumour cells further supporting the premise that skin-resident Treg cells are rapidly mobilized, controlling innate immune activation without the need for expansion of recruitment of Treg cells into the skin. In line with the rapid manifestation of Treg-cell activity in the skin, previous reports indicate that the majority of skin Treg cells express CCR4 and high levels of CD103, a molecule implicated as a marker of effector memory Treg cells,33 suggesting that the Treg cells are ready to exert their effects early in an immune response. In addition, a recent report by Rubtsov et al.34 indicated that Treg cells, present at environmental surfaces like skin and gut, keep immune responses at these sites in check through the production of the immunosuppressive cytokine, IL-10.

Animal studies show a clear increase in circulating antibody in the mite-infested Tyrosine Kinase Inhibitor Library mouse host and a rapid response to re-infestation, accompanied by a spontaneous clearance or significant reduction in mite numbers. Arlian et al. (44) demonstrated that IgG antibodies to S. scabiei var. canis whole mite extract in four different infested host species and S. scabiei var. canis-infested rabbits and dogs had elevated serum levels of total immunoglobulin, IgE and IgG compared

to controls (36,44–46). Studies in sheep demonstrated that primary infestations with either S. scabiei var. ovis or Psoroptes ovis elicited significant increases in levels of IgG, IgE and IgM that were reduced with challenge infestations (47,48). Vaccination of goats with separated mite proteins invoked high levels of scabies-specific IgG but failed to induce specific IgE. In contrast, goats challenged experimentally with a primary or repeated mite challenge developed strong serum IgE and IgG antibody responses to Sarcoptes antigens (49). Antibody IgG responses to whole mite S. scabiei antigen in pigs have also been widely described using commercial ELISA tests with varying sensitivity and specificity (50–52). However, more recent results suggest that a diagnosis of sarcoptic mange in pigs may not correlate

with serum IgG against crude extract of S. scabiei (53). In summary, Dinaciclib manufacturer it appears that patients with crusted scabies have significantly elevated total and S. scabiei specific IgE levels in comparison with patients with ordinary scabies, in which weaker and more varied responses are documented. It seems the pronounced humoral response in crusted scabies is comparable to that observed for animal infestations, but in the case of crusted scabies the immune response is unprotective and unable to control or reduce the mite burden even when challenged in sequential infestations. Human skin harbours a variety of immune response-associated components that together form

the skin immune system, which consists typically of lymphocytes, Langerhans 4-Aminobutyrate aminotransferase cells, dermal dendritic cells, keratinocytes, granulocytes and skin-draining regional lymph nodes. Regulation of the skin defence mechanism is important as abnormal or inappropriate immune reactions lead to pathogenesis of skin disorders including dermatitis, psoriasis and eczema. Exposure to antigens/allergens can lead to allergic skin disorders such as atopic dermatitis, urticaria and allergic contact dermatitis. T cells play a central role in the activation and regulation of immune responses by recognizing antigen and inducing cytokine production. Furthermore, keratinocytes are known to produce pro-inflammatory cytokines IL-1, IL-6, IL-8 and TNF-α, and the immunomodulatory cytokines IL-10 and IL-12, originating from keratinocytes, are considered to be responsible for systemic effects (54).