Serum interleukin 18 and interleukin 18 binding protein in rheumatoid arthritis

OBJECTIVE: To measure serum interleukin 18 (IL18) and IL18 binding protein (IL18BP) levels in patients with inflammatory arthropathies, and to identify associations with disease status and the response to treatment. METHODS: Serum samples were obtained before and after methotrexate treatment from patients with rheumatoid arthritis (RA) and psoriatic arthritis (PsA) attending an early arthritis clinic. IL18 and IL18BP were measured by enzyme linked immunosorbent assay (ELISA). RESULTS: Sixty patients with RA and 13 with PsA were evaluated. Serum IL18 levels were significantly higher in RA than in PsA (p<0.001). After six months' treatment with methotrexate, IL18 levels were reduced, but the differences were not significant (p=0.052). In cross sectional analyses, no correlations between IL18 levels and measures of disease activity or structural damage in RA were found. In longitudinal analyses, no correlations between IL18 levels and the response to treatment or the degree of progressive joint damage were found. Similarly, IL18BP levels were raised in RA, and were not associated with measures of the clinical status or the response to treatment. CONCLUSION: Raised serum levels of IL18 are consistent with a pathophysiological role in RA. However, in this study measurement of circulating IL18 and IL18BP did not correlate significantly with clinical measures of disease activity or the response to treatment in patients with early RA.     

Targeting interleukin 18 with interleukin 18 binding protein

A novel, constitutively expressed and secreted interleukin 18 (IL18) binding protein (IL18BP) neutralises IL18. IL18BP shares many characteristics with soluble cytokine receptors of the IL1 family in that the protein exhibits specificity for IL18, belongs to the immunoglobulin-like class of receptors and has limited amino acid sequences with those of the IL1 receptor type II. However, unlike soluble cytokine receptors, IL18BP does not have a transmembrane domain and hence is not anchored to the cell membrane. IL18BP is a secreted protein and not cleaved from the cell surface. IL18BP is naturally occurring and was isolated from the urine of healthy subjects. Because IL18 is an important inducer of interferon gamma (IFNgamma), IL18BP suppresses the production of IFNgamma resulting in reduced T-helper type 1 immune responses. There are four human and two mouse isoforms-resulting from mRNA splicing and found in various cDNA libraries. Each of these IL18BP isoforms have been expressed, purified and assessed for binding and neutralisation of IL18 biological activities. Two human IL18BP isoforms exhibited the greatest affinity for IL18 with a rapid on-rate, a slow off-rate and a dissociation constant (kDa) of 399 pM. The two other isoforms with an incomplete immunoglobulin domain were unable to neutralise IL18. The two human isoforms that possess a complete immunoglobulin domain, neutralise >95% IL18 at a molar excess of two. Molecular modelling identified a large mixed electrostatic and hydrophobic binding site in the immunoglobulin domain of IL18BP, which could account for its high affinity binding to the ligand. These high affinity forms may be ideally suited for blocking IL18 in human disease. It is likely that preferential secretion of high affinity functional and non-functional isoforms of IL18BP affect the immune response and the outcome of disease.     

T lymphocyte activation in euthyroid Graves' ophthalmopathy: soluble interleukin 2 receptor release, cellular interleukin 2 receptor expression and interleukin 2 production

The present study was undertaken to examine the cellular control arm of the immune response with regard to T lymphocyte proliferation in euthyroid Graves' ophthalmopathy. Twenty patients with euthyroid Graves' ophthalmopathy (7 on antithyroid drugs and 13 on no treatment) and 18 healthy controls were studied in an infection-free period. Mitogen-stimulated cellular interleukin 2 (IL2) receptor expression, soluble interleukin 2 receptor release, and interleukin 2 production, were studied in peripheral blood mononuclear cells cultured for 24 h. The cellular IL2 receptor expression and soluble IL2 receptor release did not differ between the patients and healthy controls. In contrast, IL2 production in response to pokeweed mitogen stimulation was increased in lymphocytes from patients with Graves' ophthalmopathy. The IL2 release did not correlate with the quantities of cellular and soluble IL2 receptor. The mitogen-stimulated cellular IL2 receptor expression, IL2 receptor release, and IL2 production did not differ between patients with or without carbimazole therapy. Despite a suggested role of autoreactive T cells in mediating the development and propagation of autoimmune thyroid disease, this study fails to demonstrate a defective T lymphocyte activation state in patients with Graves' ophthalmopathy during an euthyroid state.     

Association of gene expression involving innate immunity and genetic variation in interleukin 28B with antiviral response

Innate immunity plays an important role in host antiviral response to hepatitis C viral (HCV) infection. Recently, single nucleotide polymorphisms (SNPs) of IL28B and host response to peginterferon α (PEG-IFNα) and ribavirin (RBV) were shown to be strongly associated. We aimed to determine the gene expression involving innate immunity in IL28B genotypes and elucidate its relation to response to antiviral treatment. We genotyped IL28B SNPs (rs8099917 and rs12979860) in 88 chronic hepatitis C patients treated with PEG-IFNα-2b/RBV and quantified expressions of viral sensors (RIG-I, MDA5, and LGP2), adaptor molecule (IPS-1), related ubiquitin E3-ligase (RNF125), modulators (ISG15 and USP18), and IL28 (IFNλ). Both IL28B SNPs were 100% identical; 54 patients possessed rs8099917 TT/rs12979860 CC (IL28B major patients) and 34 possessed rs8099917 TG/rs12979860 CT (IL28B minor patients). Hepatic expressions of viral sensors and modulators in IL28B minor patients were significantly up-regulated compared with that in IL28B major patients (≈ 3.3-fold, P < 0.001). However, expression of IPS-1 was significantly lower in IL28B minor patients (1.2-fold, P = 0.028). Expressions of viral sensors and modulators were significantly higher in nonvirological responders (NVR) than that in others despite stratification by IL28B genotype (≈ 2.6-fold, P < 0.001). Multivariate and ROC analyses indicated that higher RIG-I and ISG15 expressions and RIG-I/IPS-1 expression ratio were independent factors for NVR. IPS-1 down-regulation in IL28B minor patients was confirmed by western blotting, and the extent of IPS-1 protein cleavage was associated with the variable treatment response. CONCLUSION: Gene expression involving innate immunity is strongly associated with IL28B genotype and response to PEG-IFNα/RBV. Both IL28B minor allele and higher RIG-I and ISG15 expressions and RIG-I/IPS-1 ratio are independent factors for NVR.     

Interleukin 18 and interleukin 18 binding protein in patients with idiopathic thrombocytopenic purpura

To evaluate the balance of interleukin IL18 and its endogenous antagonist IL18 binding protein ( IL18BP ) in patients with idiopathic thrombocytopenic purpura (ITP), plasma IL18 , IL18BP , interferon gamma ( IFNG ) and IL4 levels, as well as platelet counts were measured in patients with active ITP ( n  = 23), ITP in remission ( n  = 21) and in healthy subjects ( n  = 24) by enzyme linked immunosorbent assay (ELISA). Using real-time quantitative polymerase chain reaction, the mRNA expression of IL18 , IL18BP , IFNG , IL4 , T-box ( TBX21 ) and GATA-binding protein 3( GATA3 ) were studied in all subjects. The results showed that IL18 and IFNG protein and mRNA levels were significantly increased in patients with active ITP than in control subjects, but that IL18BP were not significantly elevated in ITP patients, which resulted in an elevated ratio of IL18/IL18BP in patients with active disease. During remission stages, the levels of these cytokines were comparable to those of healthy controls. The elevated levels of IL18/IL18BP in plasma during active stages of disease suggest a possible role in the pathogenesis and course of ITP.     

Defective interleukin 2 production in patients after bone marrow transplantation and in vitro restoration of defective T lymphocyte proliferation by highly purified interleukin 2

Using OKT3 monoclonal antibody as a mitogen, we have studied interleukin 2 (IL2) production and proliferation in peripheral blood mononuclear cells (PBMC) of 23 patients receiving bone marrow transplants. Twenty patients were recipients of allogeneic bone marrow for treatment of hematologic malignancies, aplastic anemias (AA), or severe combined immunodeficiencies (SCID). Three patients with Hodgkin's disease or neuroblastoma received autologous bone marrow. Endogenous IL2 production was not detectable (less than 0.2 U/mL) in PBMC of 18 patients and was very low in PBMC from five patients (0.5 to 1.5 U/mL), as compared to normal controls (median 3.5 U/mL) or pretransplant patients (median 1.5 U/mL). The low IL2 production was associated with defective OKT3-induced proliferation of PBMC in 19 of 23 patients studied. In the first 6 months after BMT, 14 of 15 patients (93%) showed defective proliferation of PBMC as compared to five of eight patients (63%) tested between 7 and 18 months after BMT (P less than .1). In all but three patients, addition of highly purified human lymphocyte IL2 (hpIL2) restored OKT3-induced proliferation of PBMC to within the normal range. This study demonstrates that PBMC in patients after BMT have a defect of IL2 production but are able to express IL2 receptors in response to OKT3 antibody and to proliferate normally upon addition of hpIL2. PBMC of all patients showed similar functional defects, whether or not they received additional therapy, including various conditioning regimens prior to BMT and immunosuppressive therapy after BMT. These observations suggest that T cell defects after BMT are most likely secondary to quantitative or qualitative defects of transplanted T lymphocytes or their precursors.     

Raised serum interleukin 15 levels in Kawasaki disease

BACKGROUND: Interleukin (IL)15 is a novel cytokine that induces T cell proliferation, B cell maturation, natural killer cell cytotoxicity, and may have a pivotal role in the pathogenesis of inflammatory disease, acting upstream from tumour necrosis factor alpha (TNFalpha). Kawasaki disease (KD) is an inflammatory disease, in which serum levels of inflammatory cytokines such as TNFalpha and IL6 are increased. OBJECTIVE: To examine the serum levels of IL15 in KD and to evaluate the role of IL15 in estimating the severity of inflammation in KD. Results and conclusion: There was a significant increase in the mean (SD) serum levels of IL15 measured in the acute stage of KD (11.5 (5.8) pg/ml) compared with those in the subacute stage (1.3 (0.9) pg/ml) (p<0.01) and normal controls (0.9 (1.0) pg/ml) (p<0.01). The increase in IL15 correlated with the increase in TNFalpha (r(s)=0.66, p<0.01); however it did not correlate with the levels of erythrocyte sedimentation rate and C reactive protein, suggesting that IL15 may not be a useful marker in estimating the severity of inflammation in KD.     

Antibodies to hepatitis B virus surface antigen and interleukin 12 and interleukin 18 gene polymorphisms in hemodialysis patients

ABSTRACT: BACKGROUND: The interleukin (IL)18 rs360719 CC genotype is associated with the development of antibodies to hepatitis B virus surface antigen (anti-HBs) in hemodialysis (HD) patients. IL18 shares biological properties with IL12 in promoting the T-hepler 1 (Th1) system. We studied whether polymorphisms in the IL12A 3` untranslated region (UTR) and IL12B 3`UTR may contribute to anti-HBs development (titre [greater than or equal to] 10 IU/L) in HD patients either individually or jointly with the IL18 polymorphism. METHODS: In 518 HD patients and 240 controls the IL12A rs568408 3'UTR G > A polymorphism was genotyped by high-resolution melting curve analysis. Polymerase chain reaction restriction fragment length polymorphism was used to detect the IL12B rs3212227 3'UTR A > C and IL18 -1297 T > C rs360719 polymorphisms. The associations between the IL12A, IL12B and IL18 genotypes and the risk of impaired anti-HBs development were estimated by computing the odds ratios and their 95 % confidence intervals using logistic regression analysis. RESULTS: In the logistic regression analysis, the higher frequency of rs360719 CC individually (2.9 % in 207 patients without anti-HBs development vs 8.0 % in 311 patients with anti-HBs development, p = 0.009) and of rs360719 CC combined with rs568408 GG (p = 0.048), rs568408 GA (p = 0.035), rs568408 GG/AA (p = 0.034) or rs3212227 AA (p = 0.046) was associated with an increased chance for the development of anti-HBs in HD patients. Patients bearing both rs568408 AA and rs360719 TT had a 10.9-fold or 8.9-fold lower chance, respectively, to develop anti-HBs compared with those carrying any other genotype (p = 0.005) or those who had both wild-type rs568408 GG and rs360719 TT (p = 0.011). Carriers of both rs3212227 CC and rs360719 TC had a 4.6-fold lower chance for anti-HBs development than carriers of any other genotype (p = 0.042). CONCLUSION: Development of anti-HBs in HD patients is associated with gene polymorphisms of interleukins involved in the Th1 system.     

Elevated plasma concentrations of interferon (IFN)-gamma and the IFN-gamma-inducing cytokines interleukin (IL)-18, IL-12, and IL-15 in severe melioidosis

Interferon (IFN)-gamma plays an important role in the pathogenesis of sepsis. Production of IFN-gamma is stimulated by synergistic effects of interleukin (IL)-18, IL-12, and IL-15. To investigate the regulation of IFN-gamma production during severe gram-negative infection, the plasma concentrations of IFN-gamma, IL-18, IL-12, and IL-15 were measured in 83 patients with suspected melioidosis. The diagnosis was confirmed in 62 patients, 31 of whom had blood cultures positive for Burkholderia pseudomallei, of whom 12 died. Compared with healthy controls, patients had elevated levels of IFN-gamma, IL-18, IL-12p40, and IL-15 on admission, with significantly higher levels in blood culture-positive patients, and these levels remained elevated during the 72-h study period. In whole blood stimulated with heat-killed B. pseudomallei, anti-IL-12 had a stronger inhibitory effect than anti-IL-18 and anti-IL-15 on IFN-gamma production. This effect of anti-IL-12 was further enhanced by anti-IL-18. These data suggest that during gram-negative sepsis, IFN-gamma production is controlled at least in part by endogenous IL-18, IL-12, and IL-15.     

Implication of interleukin 18 in production of matrix metalloproteinases in articular chondrocytes in arthritis: direct effect on chondrocytes may not be pivotal

OBJECTIVE: To clarify the effect of interleukin (IL) 18 on cartilage degeneration by studying the profile of IL18 receptor (IL18R) on chondrocytes and the direct effect of IL18 on production of matrix metalloproteinases (MMPs), aggrecanases, and tissue inhibitors of metalloproteinases (TIMPs) in articular chondrocytes. METHODS: Monolayer cultured human articular chondrocytes were isolated from non-arthritic subjects and patients with rheumatoid arthritis or osteoarthritis. Gene expression of IL18, IL18Ralpha, IL18Rbeta, MMPs, and aggrecanases was detected by RT-PCR. Protein levels of IL18Ralpha were analysed by flow cytometry. Protein levels of IL18, MMPs, and TIMPs were measured by ELISA. Aggrecanase-2 mRNA expression was quantitatively analysed by real time RT-PCR. Protein levels of signalling molecules were assayed by western blotting. RESULTS: IL18 mRNA was constitutively expressed in chondrocytes, and was enhanced by IL1beta stimulation. Flow cytometric analysis showed that IL1beta, tumour necrosis factor alpha, and IL18 up regulated IL18Ralpha expression levels. The level of IL18Rbeta mRNA was much lower than that of IL18Ralpha, and was slightly up regulated by IL1beta. In chondrocytes responding to IL18, IL18 (1-100 ng/ml) slightly increased the production of MMP-1, MMP-3, and MMP-13, which was blocked by NF-kappaB inhibitor and p38 mitogen activated protein kinase inhibitor. IL18 up regulated mRNA expression of aggrecanase-2, but not aggrecanase-1. IL18 also slightly stimulated TIMP-1 production?through extracellular signal regulated kinase activation. CONCLUSION: IL18 induces production of MMPs from chondrocytes in inflammatory arthritis. Although the direct effect of IL18 on chondrocytes may not be pivotal for the induction of cartilage degeneration, IL18 seems to play some part in the degradation of articular cartilage in arthritis.     

Transgenic blockade of interleukin 6 transsignaling abrogates inflammation

The immunoregulatory cytokine interleukin6 (IL6) acts in a pro- and anti-inflammatory fashion. Synthesized by myeloid cells, fibroblasts and endothelial cells, IL6 on target cells, binds to the IL6 receptor (IL6R) and signals via complex formation with the ubiquitously expressed gp130 receptor. Paradoxically, most cells that respond to IL6 during inflammatory states do not express the IL6R and are themselves not directly responsive to the cytokine. A naturally occurring soluble form of the IL6R renders all cells responsive to IL6. This alternative signaling process is called IL6 transsignaling. Here we developed a transgenic strategy based on the overexpression of the soluble form of gp130, which specifically blocks all IL6 responses mediated by the soluble IL6R but does not affect IL6 responses via the membrane bound IL6R. In these mice, inflammatory processes are blocked as in IL6(-/-) mice, strongly arguing for a major role of the soluble IL6R during inflammation in vivo.     

Loss of transforming growth factor counteraction on interleukin 1 mediated effects in cartilage of old mice

OBJECTIVE: To investigate if a difference exists between young and old mice in the response of articular cartilage to interleukin 1 (IL1) and transforming growth factor beta (TGFbeta) alone or in combination. METHODS: The interaction of IL1 and TGFbeta was studied in cartilage of young (three months) and old mice (18 months) both in vivo and in vitro. Therefore, IL1, TGFbeta, or IL1 together with TGFbeta was injected into the knee joints of mice on days 1, 3, and 5 before harvest of the patellae on day 6. Alternatively, isolated patellae were stimulated with IL1, TGFbeta, or IL1 together with TGFbeta in culture for 48 hours. Proteoglycan (PG) synthesis and nitric oxide (NO) production were measured. RESULTS: IL1 inhibited PG synthesis and increased NO production in cartilage of both young and old mice. On the other hand, TGFbeta stimulated PG synthesis and reduced NO production in both age groups. Importantly, TGFbeta was able to counteract IL1 mediated effects on PG synthesis and NO production in young but not in old mice. CONCLUSIONS: Contrary to the findings in young mice, the cartilage of old animals does not antagonise IL1 effects via TGFbeta. This loss of responsiveness to the pivotal cytokine TGFbeta on effects of IL1 can be important in the initiation and progression of osteoarthritis (OA).     

Limited use of interleukin 28B in the setting of response-guided treatment with detailed on-treatment virological monitoring

A single-nucleotide polymorphism upstream of the interleukin-28B (IL28B) gene is associated with pegylated interferon-alfa-induced viral clearance in hepatitis C virus (HCV) genotype 1 patients. Using a well-characterized cohort of patients randomized to standard versus response-guided therapy, we studied whether the favorable CC type allows shortening of treatment duration. Association with viral kinetics, sustained viral response (SVR), and predictors of response were also analyzed. In the original study, 696 patients were randomized to either standard or variable therapy of 24, 48, or 72 weeks according to first undetectable HCV RNA. Association between IL28B determined by genotyping rs12979860 and end of treatment response and SVR by treatment arm was tested; baseline predictors of response were analyzed using multiple logistic regression. A total of 454 patients were evaluated. The frequency of IL28B type was CC = 29%, CT = 53%, TT = 18%. CC type was strongly associated with rapid virological response (RVR) as well as higher rates of week 8 and week 12 response. CC type was associated with SVR in both arms. In patients with RVR, SVR was high and IL28B type was not associated with SVR. In RVR patients, there was no significant difference in SVR or relapse rates after 24 or 48 weeks by IL28B type. Among non-RVR patients, CC type was associated with SVR at a higher rate than CT/TT, both in standard and variable analysis. However, when week 8 and week 12 responders were considered separately, IL28B type was no longer predictive of SVR. Few CC patients remained viremic beyond week 8 to allow the analysis of relationships between IL28B type and extended treatment. Conclusion: In HCV-1 patients, the favorable CC type strongly predicted higher rates of on-treatment virological milestones and SVR. However, achievement of on-treatment virological milestones was the critical factor in determining outcome. IL28B type appeared to have limited potential for response-guided treatment strategies.     

Age-related decline in interleukin 2 production in response to influenza vaccine

Articles in the recent literature document an abnormal antibody response in elderly persons to influenza vaccination. Several studies have presented evidence to show that immune dysfunction in aged mice and humans may be due to a defect in the production of interleukin 2 (IL2) by helper T cells (TH). Cultures of peripheral blood mononuclear cells (PBMC) were prepared from blood samples taken at eight weeks after vaccination (0.5 mL of Armand-Frappier, 15 micrograms/0.5 mL each of A/Taiwan/1/86, A/Leningrad/360/86, and B/Ann Arbor/1/86 administered in the fall of 1987) from a group of elderly men and a young control group. Peripheral blood mononuclear cells were frozen in 10% dimethyl sulfoxide (DMSO) until all the cells were cultured. After stimulation with a 1/320 dilution of the same influenza vaccine, cultures of PBMC from young controls showed a significantly greater increase in IL2 production than the cultures of PBMC from the elderly group of patients. This was statistically significant at both day 3 (P less than .01) and day 5 (P less than .05) of culture using the Mann-Whitney U test. Previous experiments that have shown defective IL2 production related to aging have used potent mitogens such as concanavalin A and phytohemagglutinin to stimulate TH. This study provides evidence that defective IL2 production may also occur in response to physiologic antigenic stimulation and may be one explanation for the reduced efficacy of influenza vaccination in elderly persons.     

Clinical value of interleukin 1- and interleukin 2-determinations in patients after kidney transplantation

In a retrospective study of allograft rejections in renal transplant recipients we examined the value of cytokine production monitoring. Interleukin 1 (IL 1) and interleukin 2 (IL 2) activities were determined in supernatants of mitogen-stimulated peripheral blood lymphocytes in 8 renal transplant recipients serially for a period up to 60 days after transplantation. LPS-induced IL 1 as well as PHA-induced IL 2 production in patients after renal transplantation were significantly decreased in comparison to healthy controls. Seven episodes of cellular rejection were diagnosed in renal allograft recipients during this time, only 4 rejection episodes, however, were associated with a rise in the IL 1 and simultaneous IL 2 production occurred for 2 up to 3 days before the diagnosis of rejection. Moreover there were 12 instances in which an elevation of IL 1 and IL 2 production was found independently from the rejection. In 8 cases the augmentation of IL 1 and IL 2 production could be associated with clinical infections. We conclude from these results that a cytokine monitoring for the diagnosis of allograft rejection does not seem to be useful.     

Acute lymphoblastic leukemia and non-Hodgkin's lymphoma of T lineage: colony-forming cells retain growth factor (interleukin 2) dependence

The regulatory role of interleukin 2 (IL 2) in the proliferation of T acute lymphoblastic leukemia (T-ALL) and T non-Hodgkin's lymphoma (T- NHL) cells from six individual patients was analyzed in a colony culture system to which pure recombinant IL 2, and the lectin phytohemagglutinin (PHA) or the phorbol ester 12-O-tetradecanoyl phorbol-13-acetate (TPA), had been added. The proliferative response was correlated with the inducibility of receptors for IL 2 on the surface membrane of T-ALL and T-NHL cells by incubation with TPA or PHA for 18 hours. Leukemic T cell colonies, identified by immunophenotyping or cytogenetic analysis, appeared in vitro following TPA and IL 2 stimulation in all six cases. Accordingly, receptors for IL 2, initially absent from the cell surface, were found on high proportions of the T-ALL and T-NHL cells after in vitro exposure to TPA. In contrast, colony formation stimulated by PHA and the induction of IL 2 receptors by PHA were limited to the one case of T-NHL with the mature thymocyte immunophenotype. The cells from the other patients, expressing common or prothymocyte phenotypes, did not respond to PHA. No colonies were formed in any of these cases when PHA or TPA was withheld from the IL 2-containing cultures. Although colony growth depended absolutely on exogenous IL 2 in three cases (ALL), in the three other cases (one ALL, two NHL) some colonies grew also when no IL 2 had been added to the cultures. Upon further analysis of the cells of one of the latter patients, it was found that the cells produced IL 2 and proliferated in response to this endogenous IL 2. The results from this study indicate that the requirements of endogenous v exogenous IL 2 for cell proliferation in T-ALL and T-NHL and IL 2 receptor activation by PHA and TPA vary from patient to patient. In addition, they support the notion that T-ALL and T-NHL cells have not lost dependence on IL 2 and IL 2 receptor activation for in vitro growth.     

Dehydroepiandrosterone suppresses interleukin 10 synthesis in women with systemic lupus erythematosus

OBJECTIVE: To study the effects of dehydroepiandrosterone (prasterone, DHEA) 200 mg/day on cytokine profiles in adult women with active systemic lupus erythematosus (SLE). METHODS: In a double blind, randomised, placebo controlled study conducted as part of a larger multicentre study, 30 adult women with active SLE received oral DHEA 200 mg/day or placebo for 24 weeks. Baseline prednisone (<10 mg/day) and other concomitant SLE medications were to remain constant. The levels of cytokines including interleukin (IL) 1, IL2, interferon gamma, IL4, and IL10 were determined by ELISA. The mean change from baseline to 24 weeks of therapy was analysed. RESULTS: The two groups (DHEA n = 15; placebo n = 15) were well balanced for baseline characteristics. Only IL1beta and IL10 could be detected in the serum of lupus patients; however, there was no significant mean (SD) difference in serum IL1beta before and after treatment (9.94 (8.92) v 9.20 (6.49) pg/ml). IL10 demonstrated a greater and significant reduction from baseline (9.21 (9.66) to 1.89 (1.47) pg/ml in the DHEA treatment group). CONCLUSIONS: In a 24 week study of adult Chinese women with mild to moderate SLE, treatment with DHEA 200 mg once daily resulted in significant reduction of serum levels of IL10. This finding may suggest why DHEA could significantly reduce lupus flares.     

Role of interleukin 1 and interleukin 1 receptor antagonist in the mediation of rheumatoid arthritis

Chronic arthritis is characterised by chronic joint inflammation and concurrent joint erosion and destruction. The inflammatory cytokine interleukin 1 (IL1) has been shown to be a key mediator in the autoimmune disease rheumatoid arthritis (RA). Interleukin 1 mediates bone resorption and cartilage destruction, but may not play as dominant a part in joint swelling and inflammation. Interleukin 1 receptor antagonist (IL1Ra) selectively inhibits the effects of IL1 by competing for the IL1 receptor on all surfaces of the synovium. In a randomised controlled trial in 472 patients with active disease, IL1Ra 30 mg/day, 75 mg/day or 150 mg/day given by subcutaneous injection significantly reduced the signs and symptoms of RA at 24 weeks. An American College of Rheumatology (ACR) 20% response was seen in 43% of the patients treated with 150 mg/day at 24 weeks. IL1Ra was well tolerated; injection site reactions were the most common adverse event. In another trial, in 419 patients with active RA treated concomitantly with methotrexate, there were ACR 20% responses after 24 weeks in 42% of the patients treated with 1 mg/kg/day by subcutaneous injection and in 35% of those treated with 2 mg/kg/day. I1Ra offers a unique selective, targeted mechanism of action to block the IL1 mediated effects of RA.     

Predictive value of interleukin 1 gene polymorphisms for surgery

OBJECTIVES: To determine the influence of interleukin 1alpha (IL1alpha), IL1beta, and IL1 receptor antagonist gene polymorphisms on disease outcome as assessed by the need for major joint surgery within 15 years of diagnosis. PATIENTS AND METHODS: 50 patients with rheumatoid arthritis (RA) who required major joint surgery (hip, knee, or shoulder arthroplasty) within a 15 year period of disease diagnosis and 50 patients with RA with disease duration greater than 15 years and no major surgery were recruited together with 66 normal west of Scotland controls. Genomic DNA and polymerase chain reaction were used to determine polymorphisms in the genes for IL1alpha, IL1beta, and IL1 receptor antagonist. For all patients with RA recruited to the study, HLA-DR beta1 gene status was recorded as was the erythrocyte sedimentation rate (ESR) at the first ever clinic visit. RESULTS: No difference in the allele frequencies or genotypes of the IL1alpha and IL1 receptor antagonist gene polymorphisms was found between the controls and patients with RA, with or without previous surgery. IL1beta allele 2 was overrepresented in patients with RA who had undergone surgery compared with patients who had not (40% v 27%, chi(2)=4, 1df, p=0.04). ESR at the first ever clinic visit was significantly higher in those carrying allele 2 (36 mm/1st h v 22 mm/1st h, p=0.04). When patients, with or without previous surgery, who did not carry two disease associated HLA-DR beta1 alleles were compared, an increase in allele 2 was observed in the surgery cohort (42% v 25%, chi(2)=4.8, 1df, p=0.03). CONCLUSIONS: Patients who require major joint surgery were found to carry the IL1beta allele 2 more often than expected. Patients with this allele also had a higher initial ESR. This may be useful in predicting early surgery in patients who do not carry two disease associated HLA-DR beta1 alleles. Although these findings are interesting, further functional and epidemiological studies to confirm these observations are required.     

Effect of interleukin 1 and interleukin 2 on antibody production in asymptomatic hepatitis B virus (HBV) carriers

Peripheral blood mononuclear cells from asymptomatic hepatitis B virus (HBV) carriers and healthy controls were incubated with recombinant interleukin 1 (r-ILl) or recombinant interleukin 2 (r-IL2) at 37°C for 24 hours and with pokeweed mitogen (PWM) and estradiol for 72 hours. The number of antibody-producing cells was counted by hemolytic plaque assay. When the mononuclear cells were not pretreated with r-ILl or r-IL2, the number of antibody-producing cells was not increased by estradiol in asymptomatic HBV carriers. However, when the mononuclear cells were pretreated with r-IL1 or r-IL2, the number of antibody-producing cells was increased. As we have reported before, this may be have been due to the increase in the estradiol-binding capacity of the mononuclear cells by treatment with IL1 and IL2. In asymptomatic HBv carriers, IL1 and IL2 production of the monounclear cells or the response of the mononuclear cells to IL1 and IL2 is reduced. Consequently, the estradiol binding capacity is decreased, and antibody production is not increased by estradiol.