Involvement Of Interleukin-18 Research Articles

Interleukin-18 cytokine in immunity, inflammation, and autoimmunity: Biological role in induction, regulation, and treatment.

Interleukin-18 (IL-18) is a potent pro-inflammatory cytokine involved in host defense against infections and regulates the innate and acquired immune response. IL-18 is produced by both hematopoietic and non-hematopoietic cells, including monocytes, macrophages, keratinocytes and mesenchymal cell. IL-18 could potentially induce inflammatory and cytotoxic immune cell activities leading to autoimmunity. Its elevated levels have been reported in the blood of patients with some immune-related diseases, including rheumatoid arthritis, systemic lupus erythematosus, type I diabetes mellitus, atopic dermatitis, psoriasis, and inflammatory bowel disease. In the present review, we aimed to summarize the biological properties of IL-18 and its pathological role in different autoimmune diseases. We also reported some monoclonal antibodies and drugs targeting IL-18. Most of these monoclonal antibodies and drugs have only produced partial effectiveness or complete ineffectiveness in vitro, in vivo and human studies. The ineffectiveness of these drugs targeting IL-18 may be largely due to the loophole caused by the involvement of other cytokines and proteins in the signaling pathway of many inflammatory diseases besides the involvement of IL-18. Combination drug therapies, that focus on IL-18 inhibition, in addition to other cytokines, are highly recommended to be considered as an important area of research that needs to be explored.

Angiotensin AT2 Receptor is Anti-inflammatory and Reno-Protective in Lipopolysaccharide Mice Model: Role of IL-10.

Acute kidney injury (AKI) due to endotoxemic insult is predicted by the infiltration of neutrophils, monocytes and macrophages, and the release of pro-and anti-inflammatory cytokines to the site of injury. Earlier, we have demonstrated the role of angiotensin-II type 2 receptor (AT2R) stimulation in reno-protection in lipopolysaccharide (LPS)-induced inflammation and AKI in C57BL6/NHsd mice. Moreover, AT2R activation has been shown to increase the anti-inflammatory cytokine interleukin-10 (IL-10), its role in AT2R-mediated anti-inflammation and reno-protection is unknown. To address this question, in the present study mice were treated with the AT2R agonist C21 (0.3 mg/kg, intraperitoneally), LPS (5 mg/kg, intraperitoneally), or LPS with C21 pre-treatment with or without neutralizing IL-10 antibody. Treatment with C21 alone caused an increase in the plasma and kidney IL-10 levels, which peaks at 2-h, and returned to baseline at 6-h. The C21-induced IL-10 increase was blocked by the AT2R antagonist PD123319 suggesting AT2R’s involvement. LPS treatment caused a profound increase in tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) and the LPS-induced increase in these cytokines was attenuated by the C21 pre-treatment (1-h prior LPS) both in the plasma and kidney. Neutralizing IL-10 antibody treatment abrogated the C21-lowering of TNF-α and IL-6 in the kidney but not in the plasma. Similar results as related to the cytokines profiles in all the groups were also observed in the heart and spleen. The alteration in early cytokine profile prompted us to measure the markers of renal function (blood urea nitogen and urinary creatinine) in order to analyze the effect of IL-10 neutralization. However, it was too early to observe changes in renal function. Therefore, the renal function and injury markers were again measured at 24 h. Treatment with neutralizing IL-10 antibody attenuated the C21-mediated improvement in indices of the kidney function, but not the biomarkers of renal injury (kidney injury molecule-1 and neutrophil-gelatinase associated lipocalin). Collectively, our data suggest that the involvement of IL-10 in AT2R-mediated anti-inflammation and reno-protection against LPS is complex, mediating the renal cytokine profile and kidney filtration function, but not the plasma cytokine profile and renal injury markers.

Possible involvement of interleukin-18 in the pathology of hepatobiliary adverse effects related to treatment with ceritinib

BackgroundCeritinib demonstrated a statistically significant effect on the progression-free survival versus chemotherapy in patients with advanced anaplastic lymphoma kinase (ALK) rearrangement in non-small cell lung cancer (NSCLC) as the first therapy or after previous treatment with crizotinib and one or two prior chemotherapy regimens in global phase 3 studies. However, some serious adverse effects related to ceritinib therapy were reported across these clinical studies. Among them, a grade 3 and 4 increase in hepatobiliary enzymes was one of the common adverse events related to treatment with ceritinib. However, the pathology remains unclear. Previously, increased Interleukin (IL)-18 was observed in both biliary duct disease and liver disease. Therefore, we hypothesized that IL-18 is involved in the pathology of hepatobiliary adverse effects related to treatment with ceritinib and evaluated the serum IL-18.Case presentationThe patient was a 53-year-old Japanese woman that we previously reported as having severe hepatobiliary adverse effects related to ceritinib therapy. Laboratory data, CT and MRI were obtained at each time point. IL-18 was evaluated by ELISA method at each time point. Immunochemical staining of liver tissue was performed as a standard protocol using antibodies against IL-18. Our records showed that the levels of serum IL-18 increased from the early stage of hepatobiliary adverse effects related to the treatment with ceritinib and were became worse with an increase in hepatobiliary enzymes and the progression of imaging abnormalities in the bile duct. Furthermore, IL-18 positive cells were detected in the inflammatory sites around the interlobular bile duct of the liver tissue.ConclusionOur case report shows that the increase of serum IL-18 had a positive correlation with the progression of severe hepatobiliary adverse effects related to treatment with ceritinib and the involvement of IL-18 in the hepatobiliary inflammation by pathological evaluation. These results suggest that IL-18 could be a useful surrogate marker for the hepatobiliary toxicity of ceritinib. However, this is only one case report and further prospective observations will complement our data in the future.

Involvement of interleukin-18 in the pathogenesis of human eosinophilic esophagitis

IL-18 is induced in food allergy and EoE is food allergen-induced disease. Therefore, we tested the hypothesis whether IL-18 is involved in food allergen-induced EoE pathogenesis. Accordingly, we examined normal SPT+ and SPT− EoE patient blood and biopsy samples for IL-18, IL-18Rα, ICAM and VCAM expression. Herein, we show increased IL-18 level is highly significant in food allergen SPT+ compared to SPT− EoE patients. We also report that IL-18Rα+ cells and mRNA levels are induced in the esophageal biopsies of EoE patients and blood IL-18 levels correlate with esophageal eosinophilia (P<0.01). Additionally, we report that the levels of esophageal eosinophil and mast cells correlate with ICAM expression in human EoE. Mechanistically, we show that IL-18 in vitro stimulates iNKT cells and endothelial cells and induce eosinophil active cytokines IL-5 and IL-13. We provide the evidence that IL-18 is critical cytokine involved in activation of iNKT cells and ICAM in promoting human EoE.

Celiac disease and endometriosis: what is the nexus?

Celiac disease (CD) is a chronic autoimmune disorder [1]. It is an enteropathy of the proximal small intestine characterized by villous atrophy, various degrees of crypt cell hyperplasia and increased numbers of intraepithelial lymphocytes [2–4]. An altered immune response to dietary gluten is crucial for the development of CD in genetically susceptible individuals [2–4]. In CD, gluten induces both adaptive and innate immune responses [5]. CD has been connected with abnormal T helper cell type I (Th1) cytokines production [3]. In particular, it has been suggested a critical role for interleukin-18 (IL-18) and Interferon-c (IFN-c) in inducing and maintaining Th1 responses after gluten exposure [2–4]. It has been shown that IL-18 and IFN-c levels are higher in samples from CD patients compared to healthy controls [2–4]. In this respect, the presence of IL-18 within the epithelium has been related to enterocyte damage [2, 3]. IL-18 is a potent inducer of IFNc [3, 4, 6]. In this regard, it has been shown that in active CD, the early response following gluten intake characterized by high levels of IFN-c levels is driven by IL-18 [2, 3]. IFN-c has been described to play an important role in gut permeability as well as in inflammation in CD [7]. It has been observed that IFN-c secreted by gluten-activated celiac patient T cells, represents the primary effector of increased gluten peptide translocation during active disease [8]. Regarding genetic CD susceptibility, it has been revealed that most celiac patients carry the human leukocyte antigen (HLA)-DRB [18]. CD has been associated with a number of extra-gastrointestinal symptoms including endometriosis [9, 10]. This condition is a benign gynecological disorder defined by the presence of viable endometrial cells and stroma outside the uterus, principally in ovaries and uterosacral ligaments [9, 10]. The main signs are dysmenorrhea, dyspareunia, irregular bleeding and chronic pelvic pain [9]. It has been proved that CD is common and clinically relevant in women suffering from endometriosis [9, 10]. The etiology of endometriosis is not completely defined [11]. Although retrograde menstruation is the most widely accepted pathologic factor, humoral immune abnormalities have been suggested to contribute to the pathophysiology of endometriosis [11]. Similarly to CD, it has been found that endometriosis is linked to chronic local inflammatory process and presence of autoantibodies with the characteristics of an autoimmune disorder [11–13]. In this regard, it has been reported that women affected by endometriosis frequently suffer from autoimmune inflammatory diseases [12, 13]. Endometriosis shares similarities with a number of autoimmune conditions [12, 13]. Concordantly, ongoing chronic inflammation has been proposed as candidate explanation for the positive association between CD and endometriosis [9]. Interestingly, a Th1 imbalance with involvement of IL-18 and IFN-c has also been reported in endometriosis [11]. It has been seen that deep infiltrating endometriosis may be related to a Th1 response pattern [11]. In particular, IL-18 has been described as a key cytokine in developing the pathogenesis of endometriosis [14]. Increased levels of IL18 have been detected in patients with endometriosis in comparison to non-endometriotic controls [14, 15]. What is more, increased expression of IFN-c has also been proved in endometriosis [16]. IFN-c gene polymorphisms have been linked to different stages of endometriosis with R. Mormile (&) Division of Pediatrics and Neonatology, Moscati Hospital, Via A. Gramsci 3, 81031 Aversa, Italy e-mail: raffaellamormile@alice.it; raffaellamormile@libero.it

IL-10 and TNFαGenotypes in SLE

The production of two regulators of the inflammatory response, interleukin 10 (IL-10) and tumor necrosis factor α (TNFα), has been found to be deeply deregulated in SLE patients, suggesting that these cytokines may be involved in the pathogenesis of the disease. Genetic polymorphisms at the promoter regions of IL-10 and TNFα genes have been associated with different constitutive and induced cytokine production. Given that individual steady-state levels of these molecules may deviate an initial immune response towards different forms of lymphocyte activation, functional genetic variants in their promoters could influence the development of SLE. The present review summarizes the information previously reported about the involvement of IL-10 and TNFα genetic variants on SLE appearance, clinical phenotype, and outcome. We show that, in spite of the heterogeneity of the populations studied, the existing knowledge points towards a relevant role of IL-10 and TNFα genotypes in SLE.

Mechanism of T cell tolerance induction by murine hepatic Kupffer cells

The liver is known to favor the induction of immunological tolerance rather than immunity. Although Kupffer cells (KC) have been indicated to play a role in liver tolerance to allografts and soluble antigens, the mechanisms involved remain unclear. We hypothesized that KCs could promote immune tolerance by acting as incompetent antigen-presenting cells (APC), as well as actively suppressing T cell activation induced by other potent APCs. The expression of antigen presentation-related molecules by KCs was phenotyped by flow cytometry. The abilities of KCs to act as APCs and to suppress T cell activation induced by splenic dendritic cells (DC) were examined by in vitro proliferation assays using CD4(+) OVA-TCR (ovalbumin T cell receptor) transgenic T cells. We found that, compared with DCs, KCs expressed significantly lower levels of major histocompatibility complex (MHC) II, B7-1, B7-2, and CD40. This result is consistent with our observation that KCs were not as potent as DCs in eliciting OVA-specific T cell proliferation. However, KCs isolated from polyinosinic:polycytidylic acid-treated mice expressed significantly higher levels of MHC II and costimulatory molecules than did naïve KCs and could stimulate stronger T cell responses. More importantly, we found that KCs could inhibit DC-induced OVA-specific T cell activation. Further investigation of the underlying mechanism revealed that prostaglandins produced by KCs played an important role. The results ruled out the possible involvement of interleukin-10, nitric oxide, 2,3-dioxygenase, and transforming growth factor beta in KC-mediated T cell suppression. Our data indicate that KCs are a tolerogenic APC population within the liver. These findings suggest that KCs may play a critical role in regulating immune reactions within the liver and contributing to liver-mediated systemic immune tolerance. (HEPATOLOGY 2008.).

Induction of lytic cycle replication of Kaposi's sarcoma-associated herpesvirus by herpes simplex virus type 1: involvement of IL-10 and IL-4

Previously, we identified that both human herpesvirus 6 and human immunodeficiency virus type 1 Tat were important cofactors that activated lytic cycle replication of Kaposi's sarcoma-associated herpesvirus (KSHV). Here, we further investigated the potential of herpes simplex virus type 1 (HSV-1) to influence KSHV replication. We demonstrated that HSV-1 was a potentially important factor in the pathogenesis of Kaposi's sarcoma, as determined by production of lytic phase mRNA transcripts, viral proteins and infectious viral particles in BCBL-1 cells. These results were further confirmed by an RNA interference experiment using small interfering RNA targeting KSHV ORF50 and a luciferase reporter assay testing ORF50 promoter-driven luciferase activity. Finally, we discovered that production of human interleukin-10 (IL-10) and IL-4 partially contributed to HSV-1-induced KSHV replication. Our data present the first direct evidence that HSV-1 can activate KSHV lytic replication and suggest a role of HSV-1 in KSHV pathogenesis.

Stress induced morphological microglial activation in the rodent brain: Involvement of interleukin-18

The present study investigated the possibility that acute stress might activate microglial cells. Wistar rats were exposed to 2 h period of restraint combined with water immersion stress prior to brain analysis by immunohistochemistry with OX-42, a marker of complement receptor CR3. A single session of stress provoked robust morphological microglial activation in the thalamus, hypothalamus, hippocampus, substantia nigra and central gray. These effects appeared as early as at 1 h of exposure and were further intensified at 2 h. Morphological activation was not accompanied with changes in markers of functional activation or of inflammation including interleukin-1β (IL-1β), interleukin-6 (IL-6) and inducible nitric oxide synthase (iNOS). Similar results were obtained with mice where the effects of stress were compared in animals null for interleukin-18 (IL-18 KO), a cytokine previously demonstrated to be modulated by stress and to contribute to microglia activation. The results demonstrated significant reduction of stress-induced microglial activation in IL-18 KO mice. The present study reports evidence that physical/emotional stress may induce morphological microglial activation in the brain and this activation is in part mediated by interleukin-18.

Molecular characterization, 3D modelling and expression analysis of sea bass ( Dicentrarchus labrax L.) interleukin-10

Interleukin-10 (IL-10) is a pleiotropic cytokine generally known for its relevance in the resolution of inflammation, but that also has immunostimulatory properties. Here is described the isolation and characterization of the sea bass IL-10 (sbIL-10) cDNA and gene. The sbIL-10 gene encodes a 187 amino acid protein and comprises a five exon-four intron structure as other known IL-10 genes. Important structural residues are maintained in the sbIL-10 protein, including the four cysteines responsible for the two intra-chain disulfide bridges reported for human IL-10. The 3D structure of sbIL-10 was predicted. This first homology model of a fish IL-10 reveals a high degree of compatibility between the dimeric quaternary architectures of sbIL-10 and its mammalian counterparts. The phylogenetic analysis clusters sbIL-10 with other IL-10s, apart from IL-10-related molecules. The involvement of IL-10 in sea bass immune responses was demonstrated by investigating the expression profiles of IL-1β and IL-10 in the head-kidney and spleen following intraperitoneal injection of UV-killed Photobacterium damselae ssp. piscicida. Furthermore, involvement of IL-10 in the resolution of inflammation is for the first time suggested in fish, due to the delayed maximal mRNA levels of sbIL-10 compared to those of the pro-inflammatory IL-1β.

Neither sequence variation in the IL-10 gene promoter nor presence of IL-10 protein in the cerebral cortex is associated with Alzheimer's disease

Interleukin 10 (IL-10) is an important anti-inflammatory cytokine produced in response to neuroinflammation and might be involved in modulating the progression of Alzheimer's disease (AD) through inhibiting the action of pro-inflammatory cytokines. We have used immunohistochemistry, Western blotting, real time-PCR (RT-PCR) on frontal (BA 6/24) and temporal (BA 20–22) neocortex and hippocampus from AD and control brains as well as genetic association analysis to address the possible involvement of IL-10 in AD. Expression of IL-10 in AD and control brains at both protein and mRNA levels were detected. However, the level of expression, particularly of IL-10 protein, varied considerably in individual brains and we did not find a significant difference between AD and controls. Using direct sequencing we examined five single nucleotide polymorphisms (SNPs) (−3538, −1354, −1087, −824, −597) and two microsatellites (IL-10-G, IL-10-R) in the promoter region of the IL-10 gene. None of the identified SNPs were found to be associated with AD either individually or as haplotypes. Levels of IL-10 protein and gene expression examined also did not appear to be related to AD. Despite this being a relatively small sample, these data suggest that IL-10 does not play a major role in the development of AD.

Deficiency in CCR5 but not CCR1 protects against neointima formation in atherosclerosis-prone mice: involvement of IL-10

AbstractThe chemokine RANTES has been implicated in neointimal hyperplasia after arterial injury. We analyzed the differential role of the RANTES receptors CCR1 and CCR5 by genetic deletion in apolipoprotein E–deficient mice. Deficiency in CCR5 significantly reduced neointimal area after arterial wire injury, associated with a decrease in macrophages, CD3+ T lymphocytes, and CCR2+ cells. In contrast, CCR1 deficiency did not affect neointimal area or cell content. Deletion of CCR5 entailed an up-regulation of the anti-inflammatory cytokine interleukin 10 (IL-10) in neointimal smooth muscle cells, and its antibody blockade reversed effects in CCR5–/– mice. Conversely, proinflammatory interferon γ was increased in the neointima of CCR1–/– mice, and its blockade unmasked a reduction in macrophage recruitment. Our data indicate that CCR5 is more crucial than CCR1 for neointimal plaque formation, and that its attenuation in CCR5–/– mice is due to an atheroprotective immune response involving IL-10. This harbors important implications for targeting chemokine receptors in vascular remodeling.

The abnormal apoptosis of T cell subsets and possible involvement of IL-10 in systemic lupus erythematosus

To study the apoptosis of lymphocyte subpopulations in systemic lupus erythematosus (SLE) patients and the possible role of IL-10 in this apoptosis involved in the pathogenesis of SLE, three color fluorescence and flow cytometry were used to investigate the early apoptosis of lymphocyte subsets from freshly separated or cultured peripheral blood mononuclear cells (PBMCs). ELISA was employed to detect the levels of IL-10 in serum and the levels of sFas and sFasL in cultured PBMC supernatants, and the results of sFas and sFasL were confirmed by real-time PCR of Fas and FasL mRNA. The results showed that in cells from SLE patients, the apoptosis of CD3 +, CD4 +, and CD8 + T cells was distinctly increased, and the percentage of CD4 + cells and the CD4/CD8 ratio was significantly decreased, as compared with normal controls. The apoptosis of T lymphocytes cultured with SLE serum was markedly higher than that of cells cultured with control’s serum. Blockade of interleukin-10 (IL-10) activation by an anti-IL-10 antibody reduced the SLE serum induced apoptosis of CD4 + and CD8 + T cells. The levels of sFas and sFasL in the culture supernatant and Fas and FasL mRNA expressions in cultured cells were significantly higher in the SLE serum-cultured groups, but decreased evidently in the presence of the anti-IL-10 antibody. Above findings suggested that SLE cells showed abnormally high apoptosis of T lymphocytes, especially of the CD4 + subpopulation, resulting in a decreased CD4/CD8 ratio. The high percentage of apoptotic T cells in SLE patients may be related to the high levels of IL-10 in SLE serum, as IL-10 may induce the abnormally activated T cells to trigger apoptosis via the Fas–FasL pathway.

W09-P-004 EFfect of pravastatin on sympathetic innervation in hyperlipidemic rabbits

Inflammatory factors are thought to play a regulatory role in restenosis. Interleukin-10 (IL10) is an important anti-inflammatory cytokine with anti-atherogenic potentials. The aim of this study was to assess the effects of IL10 modulation on cuff-induced neointima formation in hypercholesterolemic APOE*3-Leiden mice.The involvement of IL10 in neointima formation was studied in a hypercholesterolemic mouse model of cuff-induced stenosis of the femoral artery by IL10 knocking-out or overexpression procedures. IL10+/− mice were crossbred with APOE*3-Leiden mice to generate hypercholesterolemic APOE*3-LeidenIL10−/− mice. To achieve IL10 overexpression in APOE*3-Leiden mice, a single intramuscular injection of a murine IL10 overexpression plasmid was performed followed by electroporation.Knocking-out IL10, in hypercholesterolemic APOE*3-Leiden mice, resulted in a significant 1.9-fold increase of neointima surface as compared to APOE*3-LeidenIL10+/+ littermates (p = 0.02). Conversely, a marked 45% inhibition on cuff-induced neointima formation was obtained after IL10 overexpression (p = 0.02). Electrodelivery of IL10 vector leads to detectable IL10 serum levels, with a sustained expression over the experimental period of 3 weeks. IL10 overexpression reduced plasma cholesterol levels in APOE*3-Leiden mice, whereas IL10 deficiency in these mice did not lead to altered cholesterol levels as compared to the IL10+/+ group. Finally, IL10 overexpression stimulated endogenous IL10 mRNA expression in the spleen and reduced the transcriptional responses of several pro-inflammatory cytokines.Here, we clearly demonstrate the role of IL10 in the development of neointima formation in hypercholesterolemic mice and the potential therapeutic effect of non-viral electrodelivery of IL10 cDNA to inhibit post-angioplasty restenosis.

Involvement of Interleukin-18 in Acute Graft-Versus-Host Disease in Mice

Interleukin (IL)-18 stimulates T helper 1 (Th1)-mediated immune responses and the development of cytotoxic T lymphocytes (CTLs). Antihost CTLs are major effectors in acute graft-versus-host disease (aGvHD), a potentially fatal complication after allogeneic stem-cell transplantation. We investigated the relevant role of IL-18 in the development of aGvHD in mice. Irradiated (C57BL/6x DBA/2) F1 (BDF1) mice transplanted with wild-type (WT) C57BL/6 (B6) splenocytes were compared with those transplanted with IL-18Ralpha-deficient B6 splenocytes with respect to Th1 development, CTL activity, severity of aGvHD, and survival. Transplantation of WT B6 spleen cells into BDF1 mice induced aGvHD that was accompanied by elevation of both serum IL-18 levels and IL-18 receptor alpha chain (IL-18Ralpha) expression on engrafted T cells. The transplantation of WT B6 cells also induced high antihost CTL activity in host spleen, whereas transplantation of IL-18Ralpha-deficient B6 cells exhibited significantly reduced antihost-specific CTL activity, indicating that IL-18Ralpha-deficient CTLs were less cytotoxic than IL-18Ralpha-expressing CTLs. Moreover, the hosts receiving transplants with the IL-18Ralpha-deficient B6 cells had fewer fatal tissue injuries and increased their survival rates as compared with those receiving transplants with WT cells. Nevertheless, Th1 development in the hosts was the same, regardless of the type of donor cells. These results suggest that Th1 induction and baseline CTL activity in aGvHD occur in the absence of IL-18, but endogenous IL-18 further accelerates aGvHD reaction to its full-blown manifestation. Thus, IL-18 may be involved in the development aGvHD by enhancing CTL activity.

Role of interleukin-18 in experimental group B streptococcal arthritis.

To assess the role of interleukin-18 (IL-18) in the evolution of septic arthritis induced by group B streptococci (GBS) in mice. CD1 mice were inoculated intravenously with 8 x 10(6) colony-forming units (CFU) of type IV GBS (strain 1/82), and administered intraperitoneally 1 hour before infection with anti-IL-18 monoclonal antibodies (0.25 mg/mouse). In a subsequent set of experiments, mice infected with a suboptimal arthritogenic dose of GBS (4 x 10(6) CFU/mouse) were administered different doses of recombinant IL-18 for 4 days, starting 1 hour after infection. Mortality, evolution of arthritis, bacterial clearance, joint histopathology, and cytokine production were examined in infected mice that did or did not receive treatment with anti-IL-18 antibodies or IL-18. IL-18 was produced during GBS infection. Neutralization of IL-18 resulted in a decrease in mortality rates, and in the incidence and severity of arthritis. Amelioration of arthritis was accompanied by a dramatic reduction in local IL-1 beta, IL-6, macrophage inflammatory protein 1 alpha (MIP-1 alpha) and MIP-2 production, and reduced bacterial burden. Administration of exogenous IL-18 resulted in increased mortality rates and increased incidence and severity of GBS arthritis, concomitant with a higher number of GBS and increased levels of IL-6, IL-1 beta, MIP-1 beta, and MIP-2 production in the joints. The present study indicated some involvement of IL-18 in the pathogenesis of GBS-induced arthritis. The role of IL-18 in joint pathology is shown by a regulatory effect on inflammatory mediator levels and local cell influx. Thus, IL-18 should be regarded as a potential therapeutic target in GBS infection and arthritis.

Involvement of Interleukin-18 in Patients on Maintenance Haemodialysis

Maintenance dialysis induces a clinical state of immunodeficiency. The pathway of circulating T cells from haemodialyzed patients is changed and characterized by an increase of Th1 cells. The unbalanced T helper differentiation derives from an altered regulation of interleukin-12 (IL-12), which represents an important inducer of Th1. IL-18 is a pro-inflammatory cytokine expressed by a variety of cell types that is structurally related to the Th1 family and shares biological properties with IL-12 as the promotion of Th1 responses. To explain the involvement of IL-18 in the typical disorders of dialysis, we analyzed IL-18 serum levels in a group of haemodialyzed patients. We enrolled 16 patients on chronic haemodialysis (HD) treatment for end-stage renal failure and 16 healthy volunteers as the control group. IL-18 levels were assessed by immunoenzymatic methods (detection limit was <12.5 pg/ml). HD patients strongly showed higher IL-18 serum levels compared to healthy donors (508.47 ± 314.39 vs. 193.44 ± 56.33 pg/ml, p < 0.005). Moreover, IL-18 levels in HD directly correlated to dialytic age (Rho = 0.544, p = 0.0419) and indirectly to Kt/V (Rho = 0.703, p = 0.0086). Our data represent the first evidence of the relation between IL-18 serum levels and HD. In the light of our results, we think that the unbalanced T helper differentiation may depend, at least in part, on an abnormality in the IL-18 production.

INCREASED PRODUCTION OF MATRIX METALLOPROTEINASE-2 IN ALVEOLAR MACROPHAGES AND REGULATION BY INTERLEUKIN-10 IN PATIENTS WITH ACUTE PULMONARY SARCOIDOSIS

Matrix metalloproteinases (MMPs) and cathepsins have been implicated in the pathogenesis of several interstitial lung diseases by their effects on inflammatory processes and extracellular matrix remodelling. T he aim of this study was to investigate whether macrophage-derived MMPs and cathepsins are involved in the pathogenesis of sarcoidosis. Therefore the release of MMP-2, MMP-9, and cathepsins B and L from alveolar macrophages (AM)in active pulmonary sarcoidosis was studied and compared to normal controls and patients with pneumonia and fibrosis. Patients with sarcoidosis (n = 11), pulmonary fibrosis (n = 7), and pneumonia (n = 9) and normal controls (n = 10) were enrolled in the study. AM were obtained bybronchoalveolar lavage and cultured without stimulation and in presence of tumor necrosis factor alpha (TNF α) and interleukin-10 (IL-10). The release of cathepsins and MMPs as well as IL-10 and TNF α was measured in the supernatant of cultured AM by fluorimetric assays and zymography. AM of patients with sarcoidosis and pneumonia spontaneously released more MMP-2 than normal controls. Stimulation with TNF α showed no effects on MMP-2 and MMP-9 production. Exogenous IL-10 led partially to an inhibition of the MMP-2 and MMP-9 release. Patients with sarcoidosis produced significantly more IL-10 and TNF α than normal controls. This was not observed in patients with fibrosis and pneumonia. The spontaneous release of cathepsins B and L did not differ between the patient groups and normal controls and was not affected by TNF α and IL-10. The data show that AM of patients with sarcoidosis and pneumonia release significant amounts of MMP-2. The endogenous production of IL-10 in AMof patients with sarcoidosis and the MMP downregulation byexogenous IL-10 suggest an involvement of IL-10 in MMP regulation. Furthermore the results suggest that the production of MMP-2 is more specific for acute lung injury, rather than for a single lung disease such as sarcoidosis.

Involvement of IL-10, an anti-inflammatory cytokine in murine liver injury induced by Concanavalin A

A mechanism of liver injury such as, viral hepatitis or autoimmune hepatitis is considered to involve the impairment of hepatocytes mainly mediated by T-cell immunity, but the roles of a variety of cytokines involved in regulation remain unclarified. We investigated the involvement of various cytokines, particularly, interleukin-10 (IL-10) which is considered to be an anti-inflammatory cytokine, in a murine model of experimental liver injury induced by Concanavalin A (Con A). The model of liver injury was made by intravenous injection of Con A (0.5 μg) through the caudal vein in 6-week-old female BALB/c mice weighting 20 g. By collecting blood before and at 1, 3, 6, 12 and 24 h after the injection of Con A, alanine aminotransferase (ALT) levels were sequentially measured, and liver tissue was sampled to examine liver injury. Furthermore, TNF-α, IL-4 and IL-10 levels were sequentially determined by enzyme-linked immunosorbent assay (ELISA). Serum ALT significantly increased between 3 and 24 h after the Con A injection, and spotty necrosis was histologically observed, suggesting mild liver injury. TNF-α and IL-4 increased soon after the injection of Con A. IL-10 increased bimodally soon after and at 12 h after the Con A injection. After neutralizing antibodies (1 μg) to IL-10 were intraperitoneally injected into the same model at 6 h before Con A treatment, serum ALT levels and the histology of the liver were examined 12 h after the Con A injection. ALT was significantly higher in the group treated with anti-IL-10 antibody (130.7±33.5 IU per I) than in the non-treated group (56.5±3.5 IU per I) ( P<0.05). Histological examination showed spotty necrosis in the group treated with anti-IL-10 antibody. These results suggest that IL-10 has inhibitory effect on liver injury in a murine model of Con A-induced experimental liver injury mediated by cellular immunity.

Involvement of interleukin-10 in the mammary cell cycles

Involvement of interleukin-10 in the mammary cell cycles