Higher Levels Of IL-17 Research Articles

Measurement Serum Levels of IFNY, IL-17 and IL-4 of Psoriasis patients in Al- Najaf City

Background: Psoriasis is an inflammatory skin disorder characterized by activation of lymphocytes, systemic and local over expression of pro-inflammatory cytokines. Objectives: The study was designed to investigate the level of cytokines in patients with psoriasis and study the correlation of the cytokines with disease severity. Methodology: Blood samples were collected of seventy patients with psoriasis for measurement of (IFNγ, IL-17 and IL-4) by ELISA technique. Results: High levels of IFNγ and IL-17 were observed in patients with psoriasis. It was found that the mean levels of IFNγ and IL-17 were significantly correlated to disease severity. Moreover, the mean level of IL-4 in psoriatic patient was found to decrease significantly according to graded severity of the disease. Statistical analysis was done by using SPSS (statistical package for social sciences) in which T-test and ANOVA test were used and chi- square (X2) test for categorical data. Conclusion: The study concluded that the level of IFNγ and IL-17 may play a key role as an indicator in the immunopathogenesis of psoriasis and markers of disease activity. Recommendation: Using another cytokines and study effect of these cytokines with disease severity.

What is the impact of Th1/Th2 ratio, SOCS3, IL17, and IL35 levels in unexplained infertility?

Implantation necessitates complex interactions among the developing embryo, decidualizing endometrium, and developing maternal immune tolerance and/or alterations in cellular and humoral immune responses. Overstimulation of T helper 1 (Th1) or Th2 cytokines in systemic and local environments, alterations of the prevalence of IL17 and regulatory T cell (Treg) cytokines have also been suggested to contribute to the pathogenesis of implantation failure. We aimed to investigate the plasma levels of IL4, IL6, IL10, TNFα, IFNγ, TGFβ, IL17, IL35, and SOCS3 in infertile and fertile women. This case–control study was conducted with 80 women suffering from unexplained infertility and 40 fertile women. Peripheral venous blood samples were drawn on day 21 of the menstrual cycle. The extracted plasma samples were assayed by an enzyme linked immunosorbent assay. Statistical analysis was performed using SPSS version 16.0. Our main findings were as follows: despite the significantly high IL17 and IL35 plasma levels of infertile women, IL35/IL17 ratio was significantly lower in the infertile group compared with that in the fertile group; SOCS3 plasma levels showed an inverse relation with plasma levels of all cytokines except IL35; increased plasma IL17 levels (>3.42pg/mL) have a negative impact on fertility; TNFα/IL10, IFNγ/IL10, IFNγ/IL6, and IFNγ/IL4 ratios were significantly higher in infertile group compared with those in the fertile group. It is not possible to show the major immunological factor(s) of unexplained infertility, but our findings point out that the decreased suppressor activity of the immune system may play a role in implantation failure.

IL-17 and TNF Synergistically Modulate Cytokine Expression while Suppressing Melanogenesis: Potential Relevance to Psoriasis

Inflammation-associated pigmentation changes are extremely common, but the etiology behind this clinical observation remains elusive. Particularly, it is unclear how the myriad of cytokines known to be involved in inflammatory skin processes affect epidermal melanocytes. We sought to determine how IL-17 and TNF influence normal human melanocytes, as these two cytokines have been implicated in various skin diseases. IL-17 and TNF jointly stimulated broad inductions of cytokines , including melanoma mitogens CXCL1 and IL-8. Moreover, IL-17 and TNF synergistically inhibited pigmentation-related signaling and melanin production, and induced keratinocytes production of β-defensin 3, an antagonist for melanocortin-receptor 1. When analyzing psoriasis lesions that are known to over express IL-17 and TNF, we observed an increase in melanocyte number and a simultaneous decrease in pigmentation signaling. Furthermore, therapeutic neutralization of TNF and IL-17 with mAbs results in a rapid recovery of pigment gene expression in psoriasis lesions. These results demonstrate that IL-17 and TNF can impact both the growth and pigment production of melanocytes, which may contribute to the pigmentation changes associated with psoriasis. These findings may allow the development of novel therapeutics for pigmentary disorders and bring new insights into the immune milieu surrounding melanocytes and related neoplasms.

CD4+NKG2D+ T Cells Exhibit Enhanced Migratory and Encephalitogenic Properties in Neuroinflammation

Migration of encephalitogenic CD4+ T lymphocytes across the blood-brain barrier is an essential step in the pathogenesis of multiple sclerosis (MS). We here demonstrate that expression of the co-stimulatory receptor NKG2D defines a subpopulation of CD4+ T cells with elevated levels of markers for migration, activation, and cytolytic capacity especially when derived from MS patients. Furthermore, CD4+NKG2D+ cells produce high levels of proinflammatory IFN-γ and IL-17 upon stimulation. NKG2D promotes the capacity of CD4+NKG2D+ cells to migrate across endothelial cells in an in vitro model of the blood-brain barrier. CD4+NKG2D+ T cells are enriched in the cerebrospinal fluid of MS patients, and a significant number of CD4+ T cells in MS lesions coexpress NKG2D. We further elucidated the role of CD4+NKG2D+ T cells in the mouse system. NKG2D blockade restricted central nervous system migration of T lymphocytes in vivo, leading to a significant decrease in the clinical and pathologic severity of experimental autoimmune encephalomyelitis, an animal model of MS. Blockade of NKG2D reduced killing of cultivated mouse oligodendrocytes by activated CD4+ T cells. Taken together, we identify CD4+NKG2D+ cells as a subpopulation of T helper cells with enhanced migratory, encephalitogenic and cytotoxic properties involved in inflammatory CNS lesion development.

To the Editor IL‐17, an important prognostic factor and potential therapeutic target for breast cancer?

To the Editor IL‐17, an important prognostic factor and potential therapeutic target for breast cancer?

T‐bet is essential for Th1‐mediated, but not Th17‐mediated, CNS autoimmune disease

T cells that produce both IL-17 and IFN-γ, and co-express ROR-γt and T-bet, are often found at sites of autoimmune inflammation. However, it is unknown whether this co-expression of T-bet with ROR-γt is a prerequisite for immunopathology. We show here that T-bet is not required for the development of Th17-driven experimental autoimmune encephalomyelitis (EAE). The disease was not impaired in T-bet−/− mice and was associated with low IFN-γ production and elevated IL-17 production among central nervous system (CNS) infiltrating CD4+ T cells. T-bet−/− Th17 cells generated in the presence of IL-6/TGF-β/IL-1 and IL-23 produced GM-CSF and high levels of IL-17 and induced disease upon transfer to naïve mice. Unlike their WT counterparts, these T-bet−/– Th17 cells did not exhibit an IL-17→IFN-γ switch upon reencounter with antigen in the CNS, indicating that this functional change is not critical to disease development. In contrast, T-bet was absolutely required for the pathogenicity of myelin-responsive Th1 cells. T-bet-deficient Th1 cells failed to accumulate in the CNS upon transfer, despite being able to produce GM-CSF. Therefore, T-bet is essential for establishing Th1-mediated inflammation but is not required to drive IL-23-induced GM-CSF production, or Th17-mediated autoimmune inflammation.

Pivotal Role of the 5-Lipoxygenase Pathway in Lung Injury after Experimental Sepsis

Postsepsis lung injury is a common clinical problem associated with significant morbidity and mortality. Leukotrienes (LTs) are important lipid mediators of infection and inflammation derived from the 5-lipoxygenase (5-LO) metabolism of arachidonate with the potential to contribute to lung damage after sepsis. To test the hypothesis that LTs are mediators of lung injury after sepsis, we assessed lung structure, inflammatory mediators, and mechanical changes after cecal ligation and puncture surgery in wild-type (WT) and 5-LO knockout (5-LO(-/-)) mice and in WT mice treated with a pharmacologic LT synthesis inhibitor (MK886) and LT receptor antagonists (CP105,696 and montelukast). Sixteen hours after surgery, WT animals exhibited severe lung injury (by histological analysis), substantial mechanical impairment (i.e., an increase in static lung elastance), an increase in neutrophil infiltration, and high levels of LTB4, cysteinyl-LTs (cys-LTs), prostaglandin E2, IL-1β, IL-6, IL-10, IL-17, KC (CXCL1), and monocyte chemotactic protein-1 (CCL2) in lung tissue and plasma. 5-LO(-/-) mice and WT mice treated with a pharmacologic 5-LO inhibitor were significantly protected from lung inflammation and injury. Selective antagonists for BLT1 or cys-LT1, the high-affinity receptors for LTB4 and cys-LTs, respectively, were insufficient to provide protection when used alone. These results point to an important role for 5-LO products in sepsis-induced lung injury and suggest that the use of 5-LO inhibitors may be of therapeutic benefit clinically.

Thymocyte Selection Regulates the Homeostasis of IL-7–Expressing Thymic Cortical Epithelial Cells In Vivo

Thymic epithelial cells (TECs) help orchestrate thymopoiesis, and TEC differentiation relies on bidirectional interactions with thymocytes. Although the molecular mediators that stimulate medullary thymic epithelial cell (mTEC) maturation are partially elucidated, the signals that regulate cortical thymic epithelial cell (cTEC) homeostasis remain elusive. Using IL-7 reporter mice, we show that TECs coexpressing high levels of IL-7 (Il7(YFP+) TECs) reside within a subset of CD205(+)Ly51(+)CD40(low) cTECs that coexpresses Dll4, Ccl25, Ccrl1, Ctsl, Psmb11, and Prss16 and segregates from CD80(+)CD40(high) mTECs expressing Tnfrsf11a, Ctss, and Aire. As the frequency of Il7(YFP+) TECs gradually declines as mTEC development unfolds, we explored the relationship between Il7(YFP+) TECs and mTECs. In thymic organotypic cultures, the thymocyte-induced reduction in Il7(YFP+) TECs dissociates from the receptor activator of NF-κB-mediated differentiation of CD80(+) mTECs. Still, Il7(YFP+) TECs can generate some CD80(+) mTECs in a stepwise differentiation process via YFP(-)Ly51(low)CD80(low) intermediates. Il7(YFP+) TECs are sustained in Rag2(-/-) mice, even following in vivo anti-CD3ε treatment that mimics the process of pre-TCR β-selection of thymocytes to the double positive (DP) stage. Using Marilyn-Rag2(-/-) TCR transgenic, we find that positive selection into the CD4 lineage moderately reduces the frequency of Il7(YFP+) TECs, whereas negative selection provokes a striking loss of Il7(YFP+) TECs. These results imply that the strength of MHC/peptide-TCR interactions between TECs and thymocytes during selection constitutes a novel rheostat that controls the maintenance of IL-7-expressing cTECs.

The Novel Role of IL-7 Ligation to IL-7 Receptor in Myeloid Cells of Rheumatoid Arthritis and Collagen-Induced Arthritis

Although the role of IL-7 and IL-7R has been implicated in the pathogenesis of rheumatoid arthritis (RA), the majority of the studies have focused on the effect of IL-7/IL-7R in T cell development and function. Our novel data, however, document that patients with RA and greater disease activity have higher levels of IL-7, IL-7R, and TNF-α in RA monocytes, suggesting a feedback regulation between IL-7/IL-7R and TNF-α cascades in myeloid cells that is linked to chronic disease progression. Investigations into the involved mechanism showed that IL-7 is a novel and potent chemoattractant that attracts IL-7R(+) monocytes through activation of the PI3K/AKT1 and ERK pathways at similar concentrations of IL-7 detected in RA synovial fluid. To determine whether ligation of IL-7 to IL-7R is a potential target for RA treatment and to identify their mechanism of action, collagen-induced arthritis (CIA) was therapeutically treated with anti-IL-7 Ab or IgG control. Anti-IL-7 Ab treatment significantly reduces CIA monocyte recruitment and osteoclast differentiation as well as potent joint monocyte chemoattractants and bone erosion markers, suggesting that both direct and indirect pathways might contribute to the observed effect. We also demonstrate that reduction in joint MIP-2 levels is responsible for suppressed vascularization detected in mice treated with anti-IL-7 Ab compared with the control group. To our knowledge, we show for the first time that expression of IL-7/IL-7R in myeloid cells is strongly correlated with RA disease activity and that ligation of IL-7 to IL-7R contributes to monocyte homing, differentiation of osteoclasts, and vascularization in the CIA effector phase.

ERK mitogen-activated protein kinase regulates Th17 cell production of IL-10 and the pathogenesis of colitis (P3197)

Abstract Distinct from proinflamamtory Th17 cells which produce high levels of IL-17 and IL-22, and mediate the pathogenesis of inflammatory bowel disease, regulatory Th17 cells have recently been identified, which produce low levels of IL-17 but high level of IL-10. However, the factors and signaling pathways regulating Th17 production of IL-10 are still largely unclear. In this report, we investigated the role of ERK MAPK signal pathway, which is activated by both TGF-β and IL-6, in Th17 cell differentiation and IL-10 production. We demonstrated that blockade of ERK activation by both ERK inhibitor or siRNA specific for ERK activity inhibited Th17 cell development while upregulating Treg cells under Th17 polarization conditions. Inhibition of ERK decreased IL-6 induction of RORγt but enhanced TGF-β induction of Foxp3. Importantly, blockade of ERK activation promoted Th17 cell IL-10 production. ERK inhibitor-treated Th17 cells function differently from proinflamamtory Th17 cells, in that ERK inhibitor-treated Th17 cells possessed suppressive function in vitro as they inhibited naïve T cell proliferation and IFNγ production at the levels comparable to that of Tregs, and had a decreased potency to induce colitis in vivo. Collectively, our data demonstrated that the ERK pathway regulated Th17 differentiation and IL-10 production, and thus interfering with the ERK pathway could provide a therapeutic treatment for inflammatory bowel diseases and other Th17-related autoimmune diseases.

IL-17 gene transfer in vivo induces bone loss and epidermal hyperplasia with implications for psoriatic arthritis (P3377)

Abstract The IL-23/IL-17 axis has been linked with pathologic features of psoriatic arthritis, however the direct role of IL-17 on innate immune cells has not been fully elucidated. We have previously demonstrated that IL-17 in vitro contributes to arthritis pathogenesis by inducing osteoclast differentiation and bone resorption. To validate these findings we overexpressed IL-17A in vivo by combining mini-circle DNA technology with hydrodynamic delivery and performed phenotypic analysis of cell populations by FACS, qPCR, histology and in vivo imaging using nanoprobes. We identified that IL-17 induced two distinct IL-17R+ populations, CD11b+Gr1low and CD11b+Gr1high that differentially contribute to bone erosion and epidermal hyperplasia respectively. Our data show that systemic high levels of IL-17 in the serum induce RANK+/c-fms+ osteoclast precursors within the CD11b+Gr1low fraction. To address the functional importance of these precursors we performed RANKL gene transfer to IL-17 overexpressing mice and noticed a significant increase of serum TRAP that correlated with increased bone erosion by microCT. Accordingly, the increase in the CD11b+Gr1high population correlated with an induction of epidermal hyperplasia, Munro’s microabscesses and hyperproliferative keratinocytes in psoriatic lesions. Collectively our data demonstrate mechanistically the role of innate immune precursor cells in the contribution to bone loss and epidermal hyperplasia, hallmarks of PsA.

Interleukin-7 HIV Transmission to Cervico-Vaginal Tissue in vivo

The majority of HIV-1 infections in women transmit through vaginal intercourse, in which virus-containing semen is deposited on the cervico-vaginal mucosa. Semen is more than a mere carrier of HIV-1, since it contains many biological factors, in particular cytokines, that may affect HIV-1 transmission. The concentration of interleukin (IL)-7, one of the most prominent cytokines in semen of healthy individuals, is further increased in semen of HIV-1-infected men. Here, we investigated the potential role of IL-7 in HIV-1 vaginal transmission in an ex vivo system of human cervico-vaginal tissue. We simulated an in vivo situation by depositing HIV-1 on cervico-vaginal tissue in combination with IL-7 at concentrations comparable with those measured in semen of HIV-1-infected individuals. We found that IL-7 significantly enhanced virus replication in ex vivo infected cervico-vaginal tissue. Similarly, we observed an enhancement of HIV-1 replication in lymphoid tissue explants. Analysis of T cells isolated from infected tissues showed that IL-7 reduced CD4+ T cell depletion preventing apoptosis, as shown by the decrease in the number of cells expressing the apoptotic marker APO2.7 and the increase in the expression of the anti-apoptotic protein B-cell lymphoma (Bcl)-2. Also, IL-7 increased the fraction of cycling CD4+ T cells, as evidenced by staining for the nuclear factor Ki-67. High levels of seminal IL-7 in vivo may be relevant to the survival of the founder pool of HIV-1-infected cells in the cervico-vaginal mucosa at the initial stage of infection, promoting local expansion and dissemination of HIV infection.

Differing Effects of Interleukin-10 on Cutaneous and Pulmonary Francisella tularensis Live Vaccine Strain Infection

We investigated the role of interleukin-10 (IL-10) in cutaneous and pulmonary infection with Francisella tularensis. We found that after intradermal challenge of mice with the live vaccine strain (LVS) of F. tularensis, splenic IL-10 levels increased rapidly and reached a peak 5 days after infection. However, IL-10 expression after infection was detrimental, since IL-10(-/-) mice showed increased bacterial clearance and were resistant to an infectious dose (>10(6) CFU/mouse) that was uniformly lethal for IL-10(+/+) mice. Furthermore, IL-10(+/+) mice treated with neutralizing anti-IL-10R monoclonal antibody were able to survive lethal cutaneous LVS challenge. The presence of IL-10 appeared to restrain the expression of IL-17, since high levels of splenic IL-17 were observed after intradermal LVS infection only in IL-10(-/-) mice. Furthermore, treatment with neutralizing anti-IL-17R antibody ablated the enhanced survival observed in IL-10(-/-) mice. However, neutralization of IL-10 activity in IL-17R(-/-) mice failed to provide protection. Thus, IL-10 suppresses a protective IL-17 response that is necessary for resistance to cutaneous LVS infection. Surprisingly, however, IL-10(-/-) mice were significantly more susceptible to pulmonary infection with LVS. Finally, although IL-10 is a critical and novel regulator of immunity to F. tularensis LVS infection, its effects were masked during infection with the highly virulent SchuS4 strain. Taken together, these findings suggest that differentially regulating expression of the IL-10 pathway in various tissues could ultimately have prophylactic and therapeutic benefits for protection against tularemia.

Serum concentration of IL‐17, IL‐23 and TNF‐α among patients with chronic spontaneous urticaria: association with disease activity and autologous serum skin test

Chronic spontaneous urticaria (CSU) is a common skin disorder, which is considered in a subset of patients to be an autoimmune disorder. T helper 17 (Th17) cells are crucially involved in the pathogenesis of some autoimmune diseases. Our aim was to test the association of Th17 with CSU. We examined interleukin (IL)-17, IL-23 and tumor necrosis factor-alpha (TNF-α) serum levels in CSU patients and studied their association with urticaria activity and autologous serum skin test (ASST). Serum concentration of IL-17, IL-23 and TNF-α were measured in 75 patients with CSU and 30 healthy control subjects. Disease activity was assessed by using urticaria activity score (UAS) as recommended by EAACI/GA(2)LEN/EDF/WAO Guidelines. Serum concentration of IL-17, IL-23 and TNF-α were significantly higher in CSU patients as compared with the healthy control subjects (mean: 35.51 ± 31.14 vs. 4.60 ± 1.38 pg/mL; P < 0.001, 38.95 ± 27.82 vs. 9.87 ± 4.62 pg/mL; P > 0.001 and 17.93 ± 6.05 vs. 6.87 ± 3.73 pg/mL; P = 0.004, respectively). There were significant positive correlation between serum IL-17, IL-23, TNF-α and disease activity assessed by cumulative UAS for 7 days before blood sampling. The Serum concentration of IL-17, IL-23 and TNF-α were also significantly higher in ASST positive patients than in ASST negative patients. Our results showed high serum levels of IL-17, IL-23 and TNF-α among CSU patients which may highlight a functional role of these cytokines in the pathogenesis of this important and common skin disease. It also may provide the rationale for new treatment strategies in chronic urticaria.

Cytokines and T cells in atopic dermatitis

Atopic dermatitis (AD) is an inflammatory disorder of the skin characterized by an impaired immune response. Several effector T cell subsets, such as pro-inflammatory cells like Th9, Th17 and Th22 cells, expressing high levels of IL-9, IL-17 and IL-22, together with the anti-inflammatory, immuno-modulating Treg cells constitutively producing IL-10, seem to play a role in this condition. IL-9 and IL-9 receptors are significantly increased in lesional AD skin compared to normal control skin. In addition, some polymorphisms in IL-9 and IL-9r genes have been associated with AD. The role of IL-17 and IL-17-producing T cells remains under debate and conflicting data are available. IL-22-producing T-cells seem to correlate with the severity of the AD. The number and function of Treg cells, producing IL-10, have been widely investigated in AD with conflicting results. Other studies suggest that high levels of IL-31 or low levels of IL-21 might be involved in the pathogenesis of AD. This review was undertaken in order to provide a better understanding of the relevance of certain cytokines in AD. We have analysed the new insight into the pathogenesis of AD, with special attention to those cytokines produced by the different T cell subpopulations.

Pitfalls in determining the cytokine profile of human T cells

Secretion of cytokines by T cells in vitro can be influenced by the methods chosen for T cell activation. However, the awareness of this fact appears insufficient. Two of the most widely applied methods for activation of T cells are phorbol 12-myristate 13-acetate (PMA) together with Ionomycin or anti-CD3/anti-CD28 stimulation. We analyzed production of IL-4, IFN-γ, IL-17 and IL-10 by a panel of human CD4 T-cell clones isolated from intestinal biopsies using the Bio-Plex™ assay and also flow-cytometry for the latter three cytokines. Higher levels of IL-17 and IFN-γ were produced by stimulation with PMA/Ionomycin compared to anti-CD3/anti-CD28. Some T-cell clones which were assigned to produce both cytokines by stimulation with PMA/Ionomycin, were only assigned to produce IFN-γ by anti-CD3/anti-CD28 stimulation. IL-10 production was higher after anti-CD3/anti-CD28 stimulation. Furthermore the dose response curve for PMA/Ionomycin differed for IL-10 compared to IL-17 and IFN-γ as it was biphasic with no IL-10 production at higher PMA/Ionomycin concentrations. These results demonstrated that the cytokine profile may be differently determined depending on the assay and conditions used and illustrate that care should be taken when designing and interpreting studies of cytokine production by T cells.

Interleukin-7 Facilitates HIV-1 Transmission to Cervico-Vaginal Tissue ex vivo

The majority of HIV-1 infections in women occur through vaginal intercourse, in which virus-containing semen is deposited on the cervico-vaginal mucosa. Semen is more than a mere carrier of HIV-1, since it contains many biological factors, in particular cytokines, that may affect HIV-1 transmission. The concentration of interleukin (IL)-7, one of the most prominent cytokines in semen of healthy individuals, is further increased in semen of HIV-1-infected men. Here, we investigated the potential role of IL-7 in HIV-1 vaginal transmission in an ex vivo system of human cervico-vaginal tissue. We simulated an in vivo situation by depositing HIV-1 on cervico-vaginal tissue in combination with IL-7 at concentrations comparable with those measured in semen of HIV-1-infected individuals. We found that IL-7 significantly enhanced virus replication in ex vivo infected cervico-vaginal tissue. Similarly, we observed an enhancement of HIV-1 replication in lymphoid tissue explants. Analysis of T cells isolated from infected tissues showed that IL-7 reduced CD4+ T cell depletion preventing apoptosis, as shown by the decrease in the number of cells expressing the apoptotic marker APO2.7 and the increase in the expression of the anti-apoptotic protein B-cell lymphoma (Bcl)-2. Also, IL-7 increased the fraction of cycling CD4+ T cells, as evidenced by staining for the nuclear factor Ki-67. High levels of seminal IL-7 in vivo may be relevant to the survival of the founder pool of HIV-1-infected cells in the cervico-vaginal mucosa at the initial stage of infection, promoting local expansion and dissemination of HIV infection.

Modulation of p38 MAPK signaling enhances dendritic cell activation of human CD4+ Th17 responses to ovarian tumor antigen

The recent finding that Th17 infiltration of ovarian tumors positively predicts patient outcomes suggests that Th17 responses play a protective role in ovarian tumor immunity. This observation has led to the question of whether Th17 cells could be induced or expanded to therapeutic advantage by tumor vaccination. In this study, we show that treatment of ovarian tumor antigen-loaded, cytokine-matured human dendritic cells (DC) with a combination of IL-15 and a p38 MAP kinase inhibitor offers potent synergy in antagonism of CD4(+) Treg induction and redirection toward CD4(+) Th17 responses that correlate with strong CD8(+) cytotoxic T lymphocyte (CTL) activation. Ovarian tumor antigen-specific CD4(+) T cells secrete high levels of IL-17 and show reduced expression of CTLA-4, PD-1, and Foxp3 following activation with IL-15/p38 inhibitor-treated DC. We further show that modulation of p38 MAPK signaling in DC is associated with reduced expression of B7-H1 (PD-L1), loss of indoleamine 2,3-dioxygenase activity, and increased phosphorylation of ERK 1/2 MAPK. These observations may allow the development of innovative DC vaccination strategies to boost Th17 immunity in ovarian cancer patients.

Th1 and Th17 but no Th2-related cytokine spectrum in the cerebrospinal fluid of children with Borrelia-related facial nerve palsy

BackgroundChemokines and cytokines in cerebrospinal fluid (CSF) and serum have been extensively studied in adults with neuroborreliosis (NB), whereas there are limited data about the pediatric population. In adults, T helper type 1 (Th1) and Th17-related cytokines were observed during acute NB. In children, the Th2 response is thought to moderate the disease course. The aim of this study was to determine the chemokine-cytokine profile in children with acute NB displaying Borrelia-related peripheral facial nerve palsy (PFNP).MethodsLuminex multiple bead technology was used for the detection of twelve cytokines and chemokines in the CSF and serum of three groups: 1) children with Borrelia-related PFNP (BPFNP); 2) children with non-borrelial “idiopathic” PFNP (NIPFNP); and 3) age-related controls.ResultsIn BPFNP, cytokines-chemokines related to a non-specific pro-inflammatory activity and specific Th1/Th17 responses were detected in CSF, and elevated IL-7 and IL-10 levels were observed in serum and CSF compared to NIPFNP and to controls. In NIPFNP, CSF findings were similar to controls; however, higher levels of IL-7 and MCP-1 were observed in serum. Higher IL-8, IL-15 and MCP-1 levels were detected in CSF compared to serum in all groups. MCP-1 and IL-8 levels in CSF were strikingly higher in BPFNP compared to the other two groups, while IL-15 levels in CSF showed no difference. In addition, in controls, increased IL-4 level was found in CSF compared to serum.ConclusionThe chemokine-cytokine profile in the CSF of children with acute NB was similar to previous studies in adults. Our data suggests that higher levels of IL-4, IL-15 and MCP-1 levels in CSF compared to serum in controls might represent a potentially protective cytokine milieu in the CNS compartment.

Role of Th17 Cells in Skin Inflammation of Allergic Contact Dermatits

Extending the classical concept considering an imbalance exclusively of T helper(h) 1 and Th2 cells on the bottom of many inflammatory diseases, Th17 cells were recently described. Today, there is sufficient experimental evidence to classify psoriasis and allergic contact dermatitis (ACD) amongst other inflammatory skin disorders as IL-17 associated diseases. In several human studies, T-cell-clones could be isolated from eczema biopsies, and high IL-17 levels were observed after challenge with allergen. In the last years, the phenotype of these IL-17 releasing T cells was in the focus of discussion. It has been suggested that Th17 could be identified by expression of retinoic acid receptor-related orphan receptor (ROR)C (humans) or RORγt (mice) and IL-17, accompanied by the absence of IFN-γ and IL-22. In cells from skin biopsies, contact allergens elevate IL-17A, IL-23, and RORC within the subset of Th cells. The indications for a participation of Th17 in the development of ACD are supported by data from IL-17 deficient mice with reduced contact hypersensitivity (CHS) reactions that could be restored after transplantation of wild type CD4+ T cells. In addition to Th17 cells, subpopulations of CD8+ T cells and regulatory T cells are further sources of IL-17 that play important roles in ACD as well. Finally, the results from Th17 cell research allow today identification of different skin diseases by a specific profile of signature cytokines from Th cells that can be used as a future diagnostic tool.