<em>Interleukin</em> (IL-) <em>27</em> is a member of IL-12 cytokine family with Th1-promoting and anti-inflammatory effects. IL-<em>27</em> has been shown to facilitate tumor-specific cytotoxic T lymphocyte (CTL) induction against various tumors. However, IL-<em>27</em> suppresses cytokine production of lymphocytes and antigen-presenting function of dendritic cells (DCs). To examine the in vivo role of IL-<em>27</em> in generation of anti-tumor immunity, we examined IL-<em>27</em>-mediated antitumor-effects using WSX-1 (IL-<em>27</em> receptor alpha chain)-deficient (WSX-1(-/-)) mice. In WSX-1(-/-) mice inoculated with B16 melanoma cells, tumor growth was higher than in wild-type (WT) mice. Accordingly, tumor-specific CTL generation was lower in WSX-1(-/-) mice than in WT mice. CTL induction in WSX-1(-/-) mice was not restored by transfer of WT DCs pulsed with TRP2 peptide, indicating that IL-<em>27</em> is directly required for generation of tumor-specific CTLs. However, when transferred into tumor-bearing mice, WSX-1(-/-) DCs pulsed with TRP2 peptide was more potent than WT DCs in tumor growth inhibition and generation of CTLs, indicating suppressive effects of IL-<em>27</em> on DC function. Finally, the combination of WT CD8(+) T cells and KO DCs is more potent in generation of antigen-specific CTLs than any other combinations. Expression of perforin gene and percentages of tumor-specific CD8(+) T cells were also the highest in the combination of WT CD8+ T cells and WSX-1(-/-) DCs. It was thus revealed that IL-<em>27</em> promotes CTL generation while suppressing DC function during generation of tumor immunity. The combination of WT T cells and IL-<em>27</em> signal-defective DCs may have therapeutic potential against tumors.

OBJECTIVE

<em>Interleukin</em>-12 (IL-12) plays an important role in antitumor immunity. <em>Interleukin</em>-<em>27</em> (IL-<em>27</em>) is a novel IL-12 family member. The present studies demonstrate that IL-<em>27</em> mediates potent antitumor activity. However, No studies have examined the association of these polymorphism with colorectal cancer (CRC). Therefore, we investigated the relationship of IL-12 and IL-<em>27</em> gene polymorphisms and CRC.

METHODS

We analyzed polymorphisms of IL-12 gene 16974 A/C and IL-<em>27</em> gene -964 A/G, 2905 T/G, 4730 T/C in 410 patients with CRC and 450 controls, using PCR-RFLP method.

RESULTS

There were no significant differences in the genotype and allele frequencies of IL-12 and IL-<em>27</em> gene polymorphisms between the group of patients with CRC and the controls. Furthermore, no association was found between IL-12 family gene polymorphisms and different clinical stages in patients with CRC.

CONCLUSIONS

These findings suggest that IL-12 and IL-<em>27</em> gene polymorphisms may not be involved in susceptibility to CRC.

Although <em>interleukin</em>-15 (IL-15) is a powerful immunomodulatory factor that has been proposed for cancer immunotherapy, its intratumoral expression may be correlated with tumor progression and/or poor clinical outcome. Therefore, neoplasias potentially sensitive to immunotherapy should be checked for their IL-15 expression and function before choosing immunotherapy protocols. Primary human renal cancer cells (RCC) express a novel form of membrane-bound IL-15 (mb-IL-15), which displays three major original properties: (a) It is expressed as a functional membrane homodimer of <em>27</em> kDa, (b) it is shed in the extracellular environment by the metalloproteases ADAM17 and ADAM10, and (c) its stimulation by soluble IL-15 receptor alpha (s-IL-15Ralpha) chain triggers a complex reverse signal (mitogen-activated protein kinases, FAK, pMLC) necessary and sufficient to ~induce epithelial-mesenchymal transdifferentiation (EMT), a crucial process in tumor progression whose induction is unprecedented for IL-15. In these cells, complete EMT is characterized by a dynamic reorganization of the cytoskeleton with the subsequent generation of a mesenchymal/contractile phenotype (alpha-SMA and vimentin networks) and the loss of the epithelial markers E-cadherin and ZO-1. The retrosignaling functions are, however, hindered through an unprecedented cytokine/receptor interaction of mb-IL-15 with membrane-associated IL-15Ralpha subunit that tunes its signaling potential competing with low concentrations of the s-IL-15Ralpha chain. Thus, human RCC express an IL-15/IL-15R system, which displays unique biochemical and functional properties that seem to be directly involved in renal tumoral progression.

OBJECTIVE

Pro-inflammatory cytokine-driven mechanisms have been implicated in vein graft failure, though little is known about the effect of hemodynamic factors and anti-inflammatory counter-regulatory mechanisms. We hypothesized that early temporal expression of the pro-inflammatory cytokine interleukin (IL)-1 beta and the anti-inflammatory cytokine IL-10 proceeds by way of wall shear stress-dependent pathways in the arterializing vein graft.

METHODS

Rabbits (n = 27) underwent bilateral jugular vein carotid interposition grafts, and simultaneous unilateral distal carotid branch ligation, to produce both low-flow and high-flow grafts in the same animal. Vein grafts were harvested at 1, 3, 7, 14, and 28 days and were assessed for architecture, wall shear stress, and cytokine messenger RNA levels (quantitative real-time two-step reverse transcription polymerase chain reaction).

RESULTS

The model resulted in an immediate 90% flow reduction (P <.001, paired t test) in the vein graft on the ligated side, and a 36% increase (P =.01) in contralateral graft flow. This persisted as approximately 15-fold flow differential throughout the 28-day period. The construction yielded a 15-fold differential in wall shear stress between low-flow and high-flow vein grafts (P <.001, two-way repeated measures analysis of variance). Intimal hyperplasia began by day 3, and was 6-fold more in low wall shear grafts by 28 days (230.6 +/- 35.4 microm intimal thickness vs 36.1 +/- 17.6 microm for low shear versus high shear grafts; P =.001). For both cytokines time independently affected mRNA expression (P <.001, global analysis of variance). Exposure of vein grafts to the arterial circulation markedly up-regulated IL-1 beta at 1 day, with significantly more induction in the low shear setting (P =.002). IL-1 beta protein localized to the developing neointima at days 1 and 3. Conversely, IL-10 slowly increased until day 14, with significantly more expression in the high shear grafts (P <.001).

CONCLUSIONS

Vein graft adaptation induces early pro-inflammatory cytokine IL-1 beta expression and delayed protective IL-10 expression (most notable under high shear conditions), both of which are modulated by wall shear. These differential temporal windows offer strategies for appropriately timed pro-inflammatory or anti-inflammatory therapies to interrupt pathologic vein graft adaptations.

CONCLUSIONS

Neointimal hyperplasia continues to limit the durability of vein bypass grafts. Emerging evidence suggests that inflammatory mechanisms drive the neointimal hyperplasic response. This study demonstrates that specific hemodynamic forces (altered wall shear stress) differentially affect early pro-inflammatory interleukin (IL)-1 beta and delayed anti-inflammatory IL-10 signaling. These distinct temporal windows for IL-1 beta and IL-10 cytokine expression offer strategies for appropriately timed pro-inflammatory and anti-inflammatory therapies to interrupt pathologic vein graft adaptations.

Sepsis is a leading cause of death, which is characterized by uncontrolled inflammatory response. In this study, we report that caveolin-1, a major component of caveolae, is a critical survival factor of sepsis. We induced sepsis using a well established sepsis animal model, cecal ligation and puncture (CLP). CLP induced 67% fatality in caveolin-1 null mice, but only <em>27</em>% fatality in wild type littermates (p = 0.015). Further studies revealed that mice deficient in caveolin-1 exhibited marked increase in tumor necrosis factor-alpha and <em>interleukin</em>-6 production 20 h following CLP treatment, indicating uncontrolled inflammatory responses in the absence of caveolin-1. Caveolin-1 null mice also had a significant increase in bacteria number recovered from liver and spleen, indicating elevated bacterial burdens. In addition, caveolin-1 null mice had a 2-fold increase in thymocyte apoptosis compared with wild type littermates, indicating caveolin-1 as a critical modulator of thymocyte apoptosis during sepsis. In conclusion, our findings demonstrate that caveolin-1 is a critical protective modulator of sepsis in mice. Caveolin-1 exerts its protective function likely through its roles in modulating inflammatory response, alleviating bacterial burdens, and suppressing thymocyte apoptosis.

Prostate cancer (PCa) is of increasing significance worldwide as a consequence of the population ageing. Fragile elderly patients may particularly benefit from noninvasive and well tolerable immunotherapeutic approaches. Preclinical studies have revealed that the immune-regulatory cytokine IL-<em>27</em> may exert anti-tumor activities in a variety of tumor types without discernable toxicity. We, thus, investigated whether IL-<em>27</em> may function as anti-tumor agent in human (h) PCa and analyzed the rationale for its clinical application. In vitro, IL-<em>27</em> treatment significantly inhibited proliferation and reduced the angiogenic potential of hPCa cells by down-regulating the pro-angiogenesis-related genes fms-related tyrosine kinase (FLT)1, prostaglandin G/H synthase 1/cyclooxygenase-1 (PTGS1/COX-1) and fibroblast growth factor receptor (FGFR)3. In addition, IL-<em>27</em> up-regulated the anti-angiogenesis-related genes such as CXCL10 and TIMP metallopeptidase inhibitor 3 (TIMP3). In vivo, IL-<em>27</em> reduced proliferation and vascularization in association with ischemic necrosis of tumors developed after PC3 or DU145 cell injection in athymic nude mice. In patients' prostate tissues, IL-<em>27</em>R was expressed by normal epithelia and low grade PCa and lost by high tumor grade and stages. Nevertheless, IL-<em>27</em>R was expressed by CD11c(+), CD4(+) and CD8(+) leukocytes infiltrating the tumor and draining lymph nodes. These data lead to the conclusion that i) IL-<em>27</em>'s anti-PCa potential may be fully exploited in patients with well-differentiated, localized IL-<em>27</em>R positive PCa, since in this case it may act on both cancerous epithelia and the tumor microenvironment; ii) PCa patients bearing high grade and stage tumor that lack IL-<em>27</em>R may benefit, however, from IL-<em>27</em>'s immune-stimulatory properties.

OBJECTIVE

To investigate changes in cytokine levels in tears of type 2 diabetics with or without retinopathy.

METHODS

Tears were collected from 15 type 2 diabetics without retinopathy (DNR), 15 patients with retinopathy (DR), and 15 age and gender matched non-diabetic controls. Tear concentrations of <em>27</em> cytokines were measured by multiplex bead immunoassay. Cytokine differences between groups, ratios of type-1 T helper (Th1)/type-2 T helper (Th2) cytokines and anti-angiogenic/pro-angiogenic cytokines were analyzed statistically.

RESULTS

The most abundant cytokine detected in tears was interferon-induced protein-10 (IP-10). In comparison with controls, IP-10 and monocyte chemoattracant protein-1 (MCP-1) levels were significantly elevated in DR (p=0.016 and 0.036, respectively) and DNR groups (p=0.021 and 0.026, respectively). Interleukin-1 (IL-1) receptor antagonist (IL-1ra) levels were significantly increased in DNR (p=0.016). Th1/Th2 cytokines interferon-gamma (IFN-γ)/IL-5 and IL-2/IL-5 ratios were significantly increased in DR compared to controls (p=0.037 and 0.031, respectively). Anti-angiogenic/angiogenic cytokines IFN-γ/MCP-1 and IL-4/MCP-1 ratios in DR and DNR were significantly decreased compared to controls (p<0.05). IL-4/IL-8 and IL-12p70/IL-8 ratios were also significantly decreased in DR compared to controls (p=0.02 and 0.045, respectively). No significant correlation was demonstrated between tear cytokine concentrations and glycosylated hemoglobin (HbA1c) or fasting plasma glucose (FPG).

CONCLUSIONS

Diabetic tears exhibited elevated levels of IP-10 and MCP-1. The Th1/Th2 cytokine balance may shift to a predominantly Th1 state in DR patients. Pro-angiogenic cytokines are more highly represented than anti-angiogenic cytokines in the tears of diabetic patients.

Novel biomarkers predicting onset or progression of nephropathy in patients with Type 2 diabetes have been recently identified. We performed a systematic review to assess the validity of biomarkers predicting onset or progression of nephropathy in patients with Type 2 diabetes in longitudinal studies. The methodological quality of the studies was scored using Standards for Reporting of Diagnostic Accuracy (STARD) criteria and the independent predictive value of the biomarkers beyond conventional risk factors was scored according to the adjustment for these risk factors. Validity of the biomarkers was determined by summarizing the methodological quality and the adjustment score. We identified 15 studies describing <em>27</em> biomarkers. Six studies had sufficient methodological quality. These studies identified 13 valid and significant markers for nephropathy in diabetes: serum <em>interleukin</em> 18, plasma asymmetric dimethylarginine; and urinary ceruloplasmin, immunoglobulin G and transferrin were considered valid markers predicting onset of nephropathy. Plasma asymmetric dimethylarginine, vascular cell adhesion molecule 1, <em>interleukin</em> 6, von Willebrand factor and intercellular cell adhesion molecule 1 were considered valid biomarkers predicting progression of nephropathy. Plasma high-sensitivity C-reactive protein, E-selectin, tissue-type plasminogen activator, von Willebrand factor and triglycerides were considered valid markers predicting onset and progression of nephropathy. Several novel biomarkers for prediction of nephropathy in diabetes have been published, which can potentially be applied in clinical practice and research in future. Because of the heterogeneous quality of biomarker studies in this field, a more rigorous evaluation of these biomarkers and validation in larger trials are advocated.

BACKGROUND

Polymyalgia rheumatica (PMR) is a systemic inflammatory disease of unknown cause that affects older individuals. Clinical symptoms respond promptly to corticosteroids, but treatment is often required for several years, frequently resulting in adverse drug effects. Guidelines for the optimal use of corticosteroids that maximize relief of symptoms but minimize adverse effects of the therapy are needed.

OBJECTIVE

To determine whether clinical or laboratory parameters in PMR could be identified that allow for stratifying patients into subsets with differences in corticosteroid requirements.

METHODS

We studied <em>27</em> patients with PMR treated with a standardized schedule of prednisone. Patients were reevaluated at monthly intervals for pain scores and physician and patient assessments. Plasma <em>interleukin</em> 6 level and the erythrocyte sedimentation rate were measured at each visit. The duration of steroid therapy and the cumulative steroid dose were calculated.

RESULTS

Based on the initial response to therapy and the duration of disease, the <em>27</em> patients could be subdivided into 3 distinct groups. Eight with low erythrocyte sedimentation rates responded rapidly and required corticosteroids for less than 1 year with rare disease flares on tapering of prednisone. Twelve others responded well initially but did not tolerate reduction to lower doses and had remitting disease of more than 1 year. Seven patients had only a partial response to the initial steroid regimen. After 4 weeks of therapy, the erythrocyte sedimentation rates improved, but levels of <em>interleukin</em> 6 remained elevated. Pretreatment pain scores were also higher in these partial responder patients (P = .05).

CONCLUSIONS

Polymyalgia rheumatica is a heterogeneous disease with variations in the treatment duration and dose of corticosteroids required for suppression of symptoms. Pretreatment erythrocyte sedimentation rate and nonresponsiveness of interleukin 6 to steroid therapy are helpful in dividing patients into subsets with different treatment requirements.

BACKGROUND

Atherosclerosis is a chronic inflammatory disease of the arterial wall. Several proinflammatory cytokines are known to promote atherosclerosis, but less is known about the physiological role of anti-inflammatory cytokines. <em>Interleukin</em> (IL)-<em>27</em> is a recently discovered member of the IL-6/IL-12 family. The IL-<em>27</em> receptor is composed of IL-<em>27</em> receptor A (WSX-1) and gp130 and is required for all established IL-<em>27</em> signaling pathways. The expression of the IL-<em>27</em> subunit Ebi3 is elevated in human atheromas, yet its function in atherosclerosis remains unknown.

OBJECTIVE

The aim of this study was to test the role of IL-<em>27</em> receptor signaling in immune cells in atherosclerosis development.

RESULTS

Atherosclerosis-prone Ldlr(-/-) mice transplanted with Il<em>27</em>ra(-/-) bone marrow and fed Western diet for 16 weeks developed significantly larger atherosclerotic lesions in aortic roots, aortic arches, and abdominal aortas. Augmented disease correlated with increased accumulation of CD45(+) leukocytes and CD4(+) T cells in the aorta, which produced increased amounts of IL-17A and tumor necrosis factor. Several chemokines, including CCL2, were upregulated in the aortas of Ldlr(-/-) mice receiving Il<em>27</em>ra(-/-) bone marrow, resulting in accumulation of CD11b(+) and CD11c(+) macrophages and dendritic cells in atherosclerotic aortas.

CONCLUSIONS

The absence of anti-inflammatory IL-<em>27</em> signaling skews immune responses toward T-helper 17, resulting in increased production of IL-17A and tumor necrosis factor, which in turn enhances chemokine expression and drives the accumulation of proatherogenic myeloid cells in atherosclerotic aortas. These findings establish a novel antiatherogenic role for IL-<em>27</em> receptor signaling, which acts to suppress the production of proinflammatory cytokines and chemokines and to curb the recruitment of inflammatory myeloid cells into atherosclerotic aortas.

The immune system plays important roles in determining the outcomes of hepatitis B virus (HBV) infection. <em>Interleukin</em>-<em>27</em> (IL-<em>27</em>) is a recently identified pro-inflammatory cytokine produced by macrophages, dendritic cells, and epithelial cells. To determine the correlation between HBV infection and IL-<em>27</em> expression, we investigated the serum IL-<em>27</em> levels in patients with HBV infection and in healthy individuals. Results showed that IL-<em>27</em> was significantly elevated in patients as compared to healthy individuals (P<0.001). IL-<em>27</em> was also detected at higher levels in patients with liver cirrhosis or hepatocellular carcinoma than those with acute hepatitis B or chronic hepatitis B (P<0.05). We also found that IL-<em>27</em> expression was influenced by HBV e antigen. In addition, our in vitro studies demonstrated that IL-<em>27</em> promoter activity, mRNA and protein expression were all stimulated in cells transfected with infectious HBV clone.

OBJECTIVE

Immunoglobulin G4 (IgG4)-related autoimmune pancreatitis (AIP) is a new clinical entity of pancreatic disorder. There are immunologic and histological abnormalities, including increased serum IgG4 levels and the infiltration of IgG4-positive plasmacytes. However, the role of IgG4 is unclear. Recently, regulatory T cells (Tregs) were reported to contribute to the development of various autoimmune diseases as well as in B-cell shifting to IgG4-producing plasmacytes. We studied Tregs in the pancreas and peripheral blood.

METHODS

We recruited 44 patients with IgG4-related AIP. For comparison, we recruited 37 patients with other pancreatic diseases and <em>27</em> healthy subjects as controls. We studied infiltrating cells in the pancreas by immunohistochemistry and analyzed inducible costimulator-positive Tregs and <em>interleukin</em> 10-positive Tregs in the peripheral blood by flow cytometry.

RESULTS

The ratio of Foxp3-positive cells to infiltrated mononuclear cells (Foxp3/Mono) in AIP patients was significantly higher than in patients with alcoholic chronic pancreatitis. In AIP, Foxp3/Mono and IgG4/Mono were positively correlated. Inducible costimulator-positive Tregs were significantly higher in AIP patients than in the patients with other pancreatic diseases and the healthy control group. Interleukin 10-positive Tregs were significantly higher in AIP patients than in the healthy control group.

CONCLUSIONS

Increased quantities of inducible costimulator-positive Tregs may influence IgG4 production in IgG4-related AIP.

<em>Interleukin</em>-<em>27</em> (IL-<em>27</em>) is a heterodimeric regulatory cytokine of the IL-12 family, which is produced by macrophages, dendritic cells, and B cells upon stimulation through innate immune receptors. Here, we described regulatory CD4(+) T cells that produce IL-<em>27</em> in response to T cell receptor stimulation during malaria infection, inhibiting IL-2 production and clonal expansion of other T cells in an IL-<em>27</em>-dependent manner. IL-<em>27</em>-producing CD4(+) T cells were Foxp3(-)CD11a(+)CD49d(+) malaria antigen-specific CD4(+) T cells and were distinct from interferon-γ (IFN-γ) producing Th1 or IL-10 producing Tr1 cells. In mice lacking IL-<em>27</em> in T cells, IL-2 production was restored and clonal expansion and IFN-γ production by specific CD4(+) T cells were improved, culminating in reduced parasite burden. This study highlights a unique population of IL-<em>27</em> producing regulatory CD4(+) T cells and their critical role in the regulation of the protective immune response against malaria parasites.

We have examined the potential of a novel cytokine, <em>interleukin</em>-<em>27</em> (IL-<em>27</em>), for gene therapy of prostate cancer. IL-<em>27</em> is the most recently characterized member of the family of heterodimeric IL-12-related cytokines and has shown promise in halting tumor growth and mediating tumor regression in several cancer models. In the present study, we examined the efficacy of a new mode of gene delivery to prostate tumors: low-frequency ultrasound irradiation or "sonoporation." We also examined the potential of IL-<em>27</em> gene delivery by sonoporation to treat and reduce the growth of prostate cancer in vivo. We used three models of immune-competent prostate adenocarcinoma and characterized the tumor-growth reduction, gene-profile expression, and effector cellular profiles. Our results suggest that IL-<em>27</em> can be effective in reducing tumor growth and can help enhance accumulation of effector cells in prostate tumors in vivo. These results are promising, because they are potentially relevant to developing novel therapies that can be translated by using the novel and effective sonoporation gene-therapy delivery strategy.

BACKGROUND

Obesity is associated with low-grade systemic inflammation, in part because of secretion of proinflammatory cytokines, resulting into peripheral insulin resistance (IR). Increased oxidative stress is proposed to link adiposity and chronic inflammation. The effects of endurance exercise in modulating these outcomes in insulin-resistant obese adults remain unclear. We investigated the effect of endurance exercise on markers of oxidative damage (4-hydroxy-2-nonenal (4-HNE), protein carbonyls (PCs)) and antioxidant enzymes (superoxide dismutase (SOD), catalase) in skeletal muscle; urinary markers of oxidative stress (8-hydroxy-2-deoxyguanosine (8-OHdG), 8-isoprostane); and plasma cytokines (C-reactive protein (CRP), interleukin-6 (IL-6), leptin, adiponectin).

METHODS

Age- and fitness-matched sedentary obese and lean men (n=9 per group) underwent 3 months of moderate-intensity endurance cycling training with a vastus lateralis biopsy, 24-h urine sample and venous blood samples taken before and after the intervention.

RESULTS

Obese subjects had increased levels of oxidative damage: 4-HNE (+37%; P0.03) and PC (+63%; P0.02); evidence of increased adaptive response to oxidative stress because of elevated levels of copper/zinc SOD (Cu/ZnSOD) protein content (+84%; P0.01); increased markers of inflammation: CRP (+737%; P0.0001) and IL-6 (+85%; P0.03), and these correlated with increased markers of obesity; and increased leptin (+262%; P0.0001) with lower adiponectin (-27%; P0.01) levels vs lean controls. Training reduced 4-HNE (-10%; P0.04), PC (-21%; P0.05), 8-isoprostane (-26%; P0.02) and leptin levels (-33%; P0.01); had a tendency to decrease IL-6 levels (-21%; P=0.07) and IR (-17%; P=0.10); and increased manganese SOD (MnSOD) levels (+47%; P0.01).

CONCLUSIONS

Endurance exercise reduced skeletal muscle-specific and systemic oxidative damage while improving IR and cytokine profile associated with obesity, independent of weight loss. Hence, exercise is a useful therapeutic modality to reduce risk factors associated with the pathogenesis of IR in obesity.

Vaccination with Mycobacterium bovis bacille Calmette-Guérin (BCG) has variable efficacy in preventing tuberculosis. We hypothesized that some of this variation might be due to differences among BCG strains. To test this, neonates in Orizaba, Mexico, were vaccinated with one of three different BCG strains (BCG-Brazil [BBCG], BCG-Denmark [DBCG], or BCG-Japan [JBCG]). One year after vaccination, peripheral blood mononuclear cells (PBMC) were obtained and recall immune responses to culture filtrate proteins (CFP) of Mycobacterium tuberculosis were evaluated using quantitative real-time PCR. CFP-activated PBMC from BBCG- and DBCG-immunized children expressed high levels of cytokines characteristic of an adaptive immune response (gamma interferon, <em>interleukin</em>-2beta [IL-12beta], and IL-<em>27</em>), while those from children immunized with JBCG did not. In contrast, vaccination with JBCG resulted in significantly greater expression of cytokines characteristic of a proinflammatory immune response (IL-1alpha, IL-1beta, IL-6, and IL-24) in PBMC activated with CFP compared to PBMC from children vaccinated with BBCG or DBCG. Thus, different strains of BCG can activate different immune pathways, which may affect long-term vaccine efficacy.

Elevated levels of Oncostatin M (OSM), an <em>interleukin</em>-6 family cytokine, have been observed in multiple sclerosis (MS), HIV-associated neurocognitive disorder (HAND), and glioblastoma (GBM); however, its effects within the CNS are not well understood. OSM regulates gene expression primarily by activating the JAK/STAT, NF-kappaB, and/or MAPK pathways, in a cell-type specific manner. In our studies, OSM induces the production of the proinflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) and inducible nitric oxide synthase (iNOS) from microglia in an NF-kappaB-dependent manner. This expression also partially requires the intermediate production of TNF-alpha and subsequent NF-kappaB activation via TNF-R1. We also demonstrate that OSM-induced TNF-alpha production from microglia is neurotoxic. The IL-12 family member, IL-<em>27</em>, suppresses OSM-mediated TNF-alpha and iNOS expression at the transcriptional level by inhibiting activation of the NF-kappaB pathway, and rescues the neurotoxicity induced by OSM-stimulated microglia. These studies are the first to demonstrate the proinflammatory effects of OSM in microglia, and also identify IL-<em>27</em> as a novel inhibitor of inflammatory processes in these cells.

The prominent role of <em>interleukin</em> (IL)-12 in inflammatory responses, especially in TH1 T cell differentiation, is well established. Moreover, in murine models of tumorigenesis, IL-12 displays remarkable antitumor properties that are mainly mediated by interferon (IFN)-γ secretion by CD4+, CD8+ T cells, natural killer (NK) or NK-T cells. Importantly, IL-12 through IFN- γ -dependent induction of the antiangiogenic factors interferon-inducible protein (IP) 10 and monokine induced by gamma interferon (MIG) contributes to tumor eradication. Recently, the structurally similar but functionally different cytokines IL-23 and IL-<em>27</em> were discovered and related to the IL-12 family of cytokines. Each of those cytokines has its own specific effects on tumor growth. Similarly to IL12p70, antitumor effects of IL-<em>27</em> are mediated via the IFN γ -IP10/MIG-axis and tumor-specific increase of cytotoxic T-lymphocyte activity. Additionally, IL-<em>27</em> itself may mimic the function of IFN- γ due to the similarity in usage of JAK/STAT signalling molecules such as STAT1. The role of IL-23 in tumor growth to date is controversial. Whether IL-23 acts pro- or anticancerogenic seems to depend on a critical balance of STAT3 signalling in both the tumor and the immune cellular microenvironment of the tumor. At least for solid tumors the promising results from preclinical studies of systemic and on-site IL-12-based therapy did not prevail in clinical studies. In future combinatorial approaches using IL-12 together with other cytokines or antiangiogenic molecules have to be evaluated. This review focuses on anticancer effects of the IL-12 family in preclinical and clinical studies with an emphasis on colorectal cancer.

<em>Interleukin</em> 35 (IL-35) is the most recently identified member of the IL-12 family of cytokines and offers the potential to be a target for new therapies for autoimmune, inflammatory, and infectious diseases. Similar to other members of the IL-12 family including IL-12, IL-23, and IL-<em>27</em>, IL-35 is composed of a heterodimer of α and β chains, which in the case of IL-35 are the p35 and Epstein-Barr virus-induced gene 3 (EBI3) proteins. However, unlike its proinflammatory relatives, IL-35 has immunosuppressive effects that are mediated through regulatory T and B cells. Although there are limited data available regarding the role of IL-35 in human autoimmunity, several murine models of autoimmunity suggest that IL-35 may have potent effects in regulating immunoreactivity via IL-10-dependent mechanisms. We suggest that similar effects are operational in human disease and IL-35-directed therapies hold significant promise. In particular, we emphasize that IL-35 has immunosuppressive ability that are mediated via regulatory T and B cells that are IL-10 dependent. Further, although deletion of IL-35 does not result in spontaneous breach of tolerance, recombinant IL-35 can improve autoimmune responses in several experimental models.

Anti-<em>interleukin</em> (IL) therapies have emerged as a major treatment for patients with moderate-to-severe psoriasis. This article reviews the up-to-date results of pivotal clinical trials targeting the <em>interleukins</em> used for the treatment of psoriasis, including IL-1, IL-2, IL-6, IL-8, IL-10, IL-12, IL-17, IL-20, IL-22, IL-23, IL-36 and bispecific biologics IL-17A/tumor necrosis factor alpha (TNF-α). Cytokines involved in the circuits of psoriasis inflammation without ongoing clinical trials are also mentioned (IL-9, IL-13, IL-15, IL-16, IL-18, IL-19, IL-21, IL-24, IL-<em>27</em>, IL-33, IL-35, IL-37, and IL-38).

<em>Interleukin</em> (IL)-<em>27</em>, a heterodimeric cytokine, has been reported to be involved in the pathogenesis of autoimmune diseases through mediating differentiation of Th1 or Th17 cells and immune cell activity or survival. However, the origin and effects of IL-<em>27</em> in joints of rheumatoid arthritis (RA) remain unclear. In this study, we investigated the distribution and anti-inflammatory roles of IL-<em>27</em> in RA synovium. The IL-<em>27</em> levels in plasma of RA patients, osteoarthritis (OA) patients, or healthy volunteers (n=15 per group) were equivalent and were at most 1 ng/ml, but the IL-<em>27</em> level in synovial fluid of RA patients (n=15, mean 0.13 ng/ml; range 0.017-0.37 ng/ml) was significantly higher than that in synovial fluid of OA patients (n=15, mean 0.003 ng/ml; range 0-0.033 ng/ml) and potentially lower than in plasma. We analyzed the protein level of IL-<em>27</em> produced by RA fibroblast-like synoviocytes (FLSs) or mononuclear cells (MNCs) from RA or OA synovial fluid or peripheral blood and showed that IL-<em>27</em> in RA joints was derived from MNCs but not from FLSs. We also found by flow cytometry that IL-<em>27</em>-producing MNCs were CD14(+), and that these CD14(+)IL-<em>27</em>(+) cells were clearly detected in RA synovium but rarely in OA synovium by immunohistochemistry. Furthermore, we demonstrated that a relatively physiological concentration of IL-<em>27</em> below 10 ng/ml suppressed the production of IL-6 and CCL20 from RA FLSs induced by proinflammatory cytokines through the IL-<em>27</em>/IL-<em>27</em>R axis. In the synovial fluid of RA, the IL-<em>27</em> level interestingly had positive correlation with the IFN-γ level (r=0.56, p=0.03), but weak negative correlation with the IL-17A level (r=-0.30, p=0.<em>27</em>), implying that IL-<em>27</em> in inflammatory joints of RA induces Th1 differentiation and suppresses the development or the migration of Th17 cells. These findings indicate that circulating IL-<em>27</em>-producing CD14(+) cells significantly infiltrate into inflamed regions such as RA synovium and have anti-inflammatory effects in several ways: both directly through the reduction of IL-6 production, and possibly through the induction of Th1 development and the suppression of Th17 development; and indirectly by regulation of recruitment of CCR6(+) cells, such as Th17 cells, through the suppression of CCL20 production. Our results suggest that such a serial negative feedback system could be applied to RA therapy.

Previous studies have suggested that mesenchymal stromal cells (MSCs) enhance the engraftment of hematopoietic stem cells and modulate the host's immune response. However, there are no randomized studies to confirm these results. Moreover, there are some concerns about the risk of tumor recurrence because of the immunosuppressive property of MSCs. We conducted an open-label, randomized phase II clinical study to assess the outcome of MSC coinfusion (3-5 × 10(5) cells/kg) during haploidentical hematopoietic stem cell transplantation. From June 2007 to June 2008, a total of 55 patients who were diagnosed with leukemia in complete remission entered the study (<em>27</em> in the treatment group and 28 in the control group). No immediate or long-term toxic side effects related to MSC infusion were noted, and the median times of white blood cell and platelet engraftment were comparable between the 2 groups. However, within 100 days, the time to a platelet concentration of >50 × 10(9) cells/L was markedly faster in the treatment group compared with the control group (22 days vs. 28 days; P = 0.036). Stromal-derived factor-1α (SDF-1α) reached a peak concentration more rapidly in the treatment group compared with the control group (8th vs. 16th day). The concentrations of SDF-1α, thrombopoietin (TPO), and <em>interleukin</em>-11 were also elevated in the MSC-treated group compared with the control group. The accumulative occurrence rate of acute graft-versus-host disease greater than grade 2 was 51.8% and 38.9% in the treatment and control groups (P = 0.422), respectively, whereas the occurrence rate of chronic graft-versus-host disease was 51.4% and 74.1% (P = 0.261), respectively. Through March 2010, which marked 2 years, the overall survival rate was 69.7% for the MSC-treated group and 64.3% for the control group (P = 0.737). Three patients in the treatment group and 2 patients in the control group experienced a hematological relapse and died of leukemia.

<AbstractText>Adoptive cell therapy (ACT) using autologous tumor-infiltrating lymphocytes (TIL) has been tested in advanced melanoma patients at various centers. We conducted a systematic review and meta-analysis to assess its efficacy on previously treated advanced metastatic cutaneous melanoma.</AbstractText><AbstractText>The PubMed electronic database was searched from inception to 17 December 2018 to identify studies administering TIL-ACT and recombinant <em>interleukin</em>-2 (IL-2) following non-myeloablative chemotherapy in previously treated metastatic melanoma patients. Objective response rate (ORR) was the primary endpoint. Secondary endpoints were: complete response rate (CRR), overall survival (OS), duration of response (DOR) and toxicity. Pooled estimates were derived from fixed or random effect models, depending on the amount of heterogeneity detected. Analysis was performed separately for high-dose (HD) and low-dose (LD) IL-2. Sensitivity analyses were performed.</AbstractText><AbstractText>Among 1,211 records screened, 13 studies (published 1988-2016) were eligible for meta-analysis. Among 410 heavily pretreated patients (some with brain metastasis), 332 received HD-IL-2 and 78 LD-IL-2. The pooled overall ORR estimate was 41% (95% CI: [35-48%]), and the overall CRR was 12% (95% CI: [7-16%]). For the HD-IL-2 group, the ORR was 43% (95% CI: [36-50%]), while for the LD-IL-2 it was 35% (95% CI: [25-45%]). Corresponding pooled estimates for CRR were: 14% (95% CI: [7-20%]) and 7% (95%CI: [1-12%]). The majority of HD-IL-2 complete responders (<em>27</em>/28) remained in remission during the extent of follow-up after CR (median: 40 months). Sensitivity analyses yielded similar results. Higher number of infused cells was associated with a favorable response. The ORR for HD-IL-2 compared favorably to the nivolumab/ipilimumab combination following anti-PD-1 failure.</AbstractText><AbstractText>TIL-ACT therapy, especially when combined with HD-IL-2, achieves durable clinical benefit and warrants further investigation. We discuss the current position of TIL-ACT in the therapy of advanced melanoma, particularly in the era of immune checkpoint blockade therapy, and review future opportunities for improvement of this approach.</AbstractText>

The relationship between autoreactivity to myelin antigens and disease progression in multiple sclerosis (MS) is not fully understood. We addressed this relationship by cross-sectionally comparing an objective measure of MS disability with immune cytokine responses to myelin proteins. The ELISPOT assay was used to determine the ex vivo interferon gamma (IFNgamma) and <em>interleukin</em>-10 (IL-10) production by peripheral blood mononuclear cells (PBMCs) in response to peptides spanning the entire proteolipid protein (PLP) and myelin basic protein (MBP) molecules in 20 patients with relapsing-remitting (RR) MS and <em>27</em> age- and sex-matched healthy controls. MS patients showed significantly higher MBP-induced IFNgamma responses and PLP-induced IL-10 responses compared with healthy controls. Using the Multiple Sclerosis Functional Composite (MSFC), a new multifactorial measure of disability, MS patients showed a significant correlation between the IFNgamma response to PLP peptides and MBP peptides, and disability. In contrast, in MS patients, there was no correlation between the MSFC and the response to unrelated control antigens or mitogens. These data show that myelin-specific T lymphocytes secreting the inflammatory cytokine IFNgamma correlate with functional impairment in MS, supporting an antigen-specific link between the immune response to myelin and disability in MS.