Interleukin-2 Receptor Beta Chain Research Articles

Does the IL-2 receptor alpha chain induced on dendritic cells have a biological function?

The IL-2 receptor (IL-2R) alpha chain (CD25), but not the IL-2R beta chain, is induced on dendritic cells (DC) by brief periods of culture. To test if this IL-2R alpha is important for DC function, DC were isolated from the spleens of mutant mice with the IL-2R alpha gene disrupted and compared with normal DC for ability to stimulate proliferation of allogeneic CD4 and CD8 T cells in culture. The IL-2R alpha null DC and the normal DC produced nearly identical proliferative responses from CD4 and from CD8 T cells. When the CD8 alpha+ and CD8 alpha- subsets of the IL-2R alpha null DC were separated, they also produced proliferative responses similar to that of their normal DC counterparts. Overall there was no evidence that the inducible IL-2R alpha on DC was required for DC development, for stimulation of T cells or for regulation of T cell responses.

Interleukin-15 as a potential regulator of the innate immune response.

Interleukin-15 (IL-15) is a newly-discovered cytokine that is produced by activated monocytes early in the course of the innate immune response. IL-15 is able to bind to components of the interleukin-2 receptor (IL-2R) despite the fact that it has no sequence homology with IL-2. IL-15 stimulates human natural killer cell proliferation, cytotoxicity, and cytokine production and can substitute for IL-2 under most conditions. In vitro studies indicate that monocyte-derived IL-15 may be an important determinant of IFN-gamma production by NK cells. In addition, IL-15 is able to promote the survival of natural killer cells under serum-free conditions. The IL-15 receptor is a heterotrimeric complex which is composed of the IL-2R beta and gamma chains in combination with a unique alpha chain (IL-15 alpha). The IL-15R alpha chain has strong sequence homology to the IL-2R alpha chain and confers high affinity binding to the IL-15R. In contrast to IL-2, transcript for IL-15 and IL-15 alpha is expressed in a number of tissues and indicates that IL-15 may be an important ligand for cells that express components of the IL-2R.

In vivo antiinfluenza virus activity of Kampo medicine Sho-Seiryu-To through mucosal immune system

The Kampo (Japanese herbal) medicine, Sho-seiryu-to, which has traditionally been used for the treatment of colds and bronchial asthma, showed potent antiinfluenza A and B virus activity through augmentation of production of antiviral IgA antibody in the nasal and bronchoalveolar cavities of mice when administrated orally before viral infection. Sho-seiryu-to also showed antiinfluenza virus activity against A virus H1N1 subtype infected in aged mice (approximately 6 months old) with an increase of antiviral IgA antibody in the bronchoalveolar wash of the treated mice by similar administration. When mice infected with mouse nonadapted influenza A virus H3N2 subtype before 14 days were secondarily infected with mouse adapted A/PR/8 (H1N1) virus and administered Sho-seiryu-to orally after the second infection, replication of the virus in both nasal and bronchoalveolar cavities was significantly inhibited. Sho-seiryu-to had no effect on the mice which were not primed with mouse nonadapted virus when administered after the infection of mouse-adapted A/PR/8 virus. Oral administration of Sho-seiryu-to caused increment of viral-specific IgA antibody secreting cells in mouse nasal lymphocyte. Sho-seiryu-to also augmented IL-2 receptor beta chain+ T-cells in Peyer's patch of the infected mice. Sho-seiryu-to also significantly reduced viral titer in the nasal washes of the infected ovalbumin-sensitized bronchial asthma model mice. Oral administration of Sho-seiryu-to before and after vaccination significantly augmented hemagglutination-inhibiting antibody in the serum by nasal inoculation of influenza HA vaccine, and significantly augmented nasal antiviral IgA antibody and bronchoalveolar and serum antiviral IgG antibodies even after secondary vaccination although induction of antiviral antibody by intranasal vaccination was insufficient without Sho-seiryu-to. These results suggest that Sho-seiryu-to is able to prevent influenza virus infection by cross-protection of subtypes of influenza A virus and B virus. Sho-seiryu-to is also useful for the treatment of influenza virus infection in hosts with a history of influenza virus infection and/or influenza vaccination and allergic pulmonary inflammation, such as bronchial asthma, and can be used as an adjuvant to nasally inoculated influenza HA vaccine.

SEMI-QUANTITATIVE POLYMERASE CHAIN REACTION ANALYSIS OF CYTOKINE AND CYTOKINE RECEPTOR GENE EXPRESSION DURING THYMIC ONTOGENY

Semi-quantitative, polymerase chain reaction (PCR) is used to uncover the patterns of cytokine transcription in the mouse thymus from day 14 to day 20 of gestation, a time period which includes many of the important events in thymic ontogeny. Interleukin 4 (IL-4), IL-7 and interferon γ (IFN-γ) mRNA is abundant from fetal day (Fd) 14–16, corresponding with the period of rapid proliferation of immature thymocytes in vivo. As the level of mRNA for these cytokines diminishes, the induction and increased expression of IL-3 and IL-2 occurs. The transcription of these cytokines correlates temporally with the period of proliferation-dependent phenotypic differentiation between Fd 16 and 20. The thymic epithelium (TE)-derived cytokines including IL-1α, IL-6 and granulocyte-macrophage colony-stimulating factor (GM-CSF) begin to be transcribed between Fd 14–15 and show peak mRNA abundance from Fd 16-20. IL-5, tumour necrosis factor α (TNF-α) and LT (lymphotoxin or TNF-β) constitute a fourth group of cytokines, along with the IL-4 receptor (IL-4R), which are transcribed at an even level throughout the fetal period. The IL-2 receptor beta chain (IL-2Rβ) and IL-10 show abundant mRNA from Fd 14–20 and have a peak level of mRNA content on Fd 16. Taken together, these studies uncover complex, overlapping patterns of cytokine gene expression. The mRNA abundance and pattern of expression of each cytokine or cytokine receptor may indicate the relative contribution that it makes to different stages of fetal thymic ontogeny.

Interleukin-15 protects from lethal apoptosis in vivo.

Interleukin-15 shares many biological activities with IL-2 and signals through the IL-2 receptor beta and gamma chains. However, IL-15 and IL-2 differ in their controls of expression and secretion, their range of target cells and their functional activities. These dissimilarities may include differential effects on apoptosis. For example, IL-2 induces or inhibits T-cell apoptosis in vitro, depending on T-cell activation, whereas IL-15 inhibits cytokine deprivation-induced apoptosis in activated T cells. Studying whether and how IL-15 modulates distinct apoptosis pathways, we show here that apoptosis induced by anti-Fas, anti-CD3, dexamethasone, and/or anti-IgM in activated human T and B cells in vitro is inhibited by IL-15 in a manner dependent on RNA synthesis. In vivo, anti-Fas-induced lethal multisystem apoptosis in mice is suppressed by a novel IL-15-IgG2b fusion protein. Only IL-15, but not IL-2, completely protected from lethal hepatic failure. Thus, IL-15 is a potent, general inhibitor of apoptosis in vitro and in vivo with intriguing therapeutic potential.

Interleukin-2 receptor beta and gamma chain dysregulation during the inhibition of CD4 T cell activation by human immunodeficiency virus-1 gp120.

We have observed that CD4 T lymphocytes from human immunodeficiency virus (HIV)-infected patients marginally express interleukin-2 receptor (IL-2R) beta and IL-2R gamma chains which are essential for IL-2 signal transduction. To analyze this observation further, we studied the influence of gp120 on the cell surface expression of IL-2R beta and IL-2R gamma by purified CD4 lymphocytes in vitro. Cross-linking of the T cell receptors of these lymphocytes initiates entry into the cell cycle as measured by CD69 and CD71 cell surface expression and [3H]thymidine incorporation. It also induces the cell surface expression of IL-2R beta and IL-2R gamma. We have shown that treatment of the CD4 T lymphocytes with HIV-1 gp120 before anti-CD3 stimulation impedes cell cycle progression as measured by reduced CD71 expression and inhibition of [3H]thymidine incorporation. Furthermore, cell surface expression of IL-2R beta and IL-2R gamma subunits, which from the functional intermediate-affinity IL-2R, are significantly inhibited. More importantly, addition of exogenous IL-2 does not restore the proliferation of the CD4 T cells treated with gp120, suggesting that cells are anergic and/or that the remaining IL-2R are not functional. This is the first study of IL-2R beta and IL-2R gamma dysregulation in the context of HIV infection and shows that CD4 is also involved in IL-2R expression.

Normal thymic selection, superantigen-induced deletion and Fas-mediated apoptosis of T cells in IL-2 receptor beta chain-deficient mice.

Mice lacking the IL-2 receptor beta chain (IL-2R beta) exhibit an autoimmune reaction characterized by generalized T cell activation, production of autoantibodies, myeloproliferation and severe anemia. T cells of IL-2R beta-/- mice were examined to elucidate the mechanism responsible for their abnormal activation and to determine how such abnormal activation might affect other cell lineages. Elevated levels of IgG, IgE and autoantibodies in IL-2R beta-/- mice were found to be associated with activated CD4+ T cells which secreted elevated levels of IL-4. Thymocytes in IL-2R beta-/- mice showed normal negative and positive selection patterns when analyzed in transgenic mice bearing a TCR specific for HY antigen, suggesting that neither IL-2 nor IL-15 is essential for thymic selection. Peripheral T cells in IL-2R beta-deficient mice underwent normal programmed cell death in response to staphylococcal enterotoxin B superantigen, in contrast to cells from mice deficient for either IL-2 or IL-2R alpha. Activated T cells in IL-2R beta-deficient mice expressed normal levels of Fas antigen and underwent normal apoptosis in response to induction with anti-Fas mAb. Thus, the accumulation of activated T cells in IL-2R beta-/- mice does not appear to be derived from abnormalities in either thymic selection or Fas-mediated apoptosis.

Induction of IL-1 beta-converting enzyme-independent apoptosis by IL-2 in human T cell lines.

Our previous study demonstrated that IL-2 suppressed growth of human T cell lines, in which the suppression was observed with members among HTLV-I-infected T cell lines independent of IL-2 for growth. In this study, we examined the molecular mechanism of IL-2-induced growth suppression with two HTLV-I-infected T cell lines; TL-OmI expressing endogenously three subunits, i.e. alpha, beta and gamma chains, of the IL-2 receptor, and an MT-1 transfectant expressing the endogenous alpha and gamma chains and exogenous beta chain. Our analysis revealed that IL-2 induced apoptosis in both T cell lines. Experiments with inhibitors for the proteases responsible for apoptosis signals showed that caspase 1 (IL-1 beta-converting enzyme) was not involved in apoptosis induced by IL-2. Other MT-1 sublines introduced with mutant beta chains demonstrated that IL-2-induced apoptosis required signals from both the serine-rich (S) region and acidic (A) region of the IL-2 receptor beta chain, which are essential but not critical for IL-2-mediated cell growth respectively. Collectively, IL-2 functions not only on growth promotion and prevention of apoptosis but also on induction of apoptosis, which may be implicated in physiological regulation of immune reactions by controlling growth and activation of T cells.

The immediate-early gene product Egr-1 regulates the human interleukin-2 receptor beta-chain promoter through noncanonical Egr and Sp1 binding sites.

The interleukin-2 IL-2 receptor beta-chain (IL-2Rbeta) is an essential component of the receptors for IL-2 and IL-15. Although IL-2Rbeta is constitutively expressed by lymphocytes, its expression can be further induced by a number of stimuli, including phorbol 12-myristate 13-acetate (PMA). We have now characterized factors that bind to an enhancer region located between nucleotides -170 and -139 of the human IL-2Rbeta promoter. Both Sp1 and Sp3 bound to the 5' portion of this region, whereas a PMA-inducible factor (PIF) mainly bound to its 3' portion and bound to the Sp binding motifs as well. In Jurkat T cells, induction of PIF DNA binding activity was rapidly induced, required de novo protein synthesis, and was sustained at a high level for at least 23 h. Interestingly, PIF was constitutively activated in human T-cell leukemia virus type 1-transformed MT-2 cells. In this paper, we demonstrate that PIF is Egr-1 based on its recognition by anti-Egr-1 antisera in gel mobility shift assays, even though the IL-2Rbeta DNA binding motif differed substantially from the canonical Egr-1 binding site. In addition, Egr-1 bound to the Sp binding site. In Jurkat cells, both sites were required for maximal IL-2Rbeta promoter activity, and in HeLaS3 cells, transfection of Egr-1 could drive activity of a reporter construct containing both sites. Moreover, Sp1 and Egr-1 could form a complex with kinetics that correlated with the production of Egr-1 in Jurkat cells upon PMA stimulation. Thus, Sp1 and Egr-1 physically and functionally cooperate to mediate maximal IL-2Rbeta promoter activity.

Genes for interleukin-2 receptor beta chain, interleukin-1 beta, and schizophrenia: no evidence for the association or linkage.

We studied a CA repeat polymorphism of the interleukin-2 receptor beta chain (IL-2RB) gene and a C/-514/T variation of the interleukin-1 beta (IL-1B) gene in Japanese schizophrenia patients. Both a case-control association study (54 patients and 54 controls) and a linkage study using six multiplex families (the number of the affected > or =4 in each family) were employed. No evidence for the association or the linkage was obtained either for the IL-2RB or IL-1B gene.

Interleukin-15 signals T84 colonic epithelial cells in the absence of the interleukin-2 receptor beta-chain.

Interleukin-15 (IL-15) shares many biological functions with interleukin-2 (IL-2) due to common receptor components. IL-15 binds to the IL-2 receptor (IL-2R) beta-chain and the common gamma-chain receptor in addition to one other IL-15 binding receptor protein (IL-15R alpha). Both IL-2R beta- and gamma-chains are required to promote cell growth in hematopoietic cells. The colonic cryptlike epithelial cell line T84 contains the common gamma-chain but lacks the IL-2R beta-chain. We report IL-15R alpha-chain mRNA in T84 cells with the use of reverse transcriptase-polymerase chain reaction. T84 and normal colonic epithelial cells bind a FLAG-IL-15 fusion protein in immunoperoxidase and flow cytometric experiments. In addition, IL-15, but not IL-2, accelerates and enhances the development of transepithelial resistance across T84 monolayers in a dose-dependent fashion. We conclude that normal and T84 colonic epithelial cells express IL-15R alpha and are able to bind IL-15. IL-15 can deliver a nonproliferative functional signal in the absence of IL-2R beta-chain in T84 cells.

Interleukin-2 induces tyrosine phosphorylation of SHP-2 through IL-2 receptor beta chain.

Coupling of interleukin-2 (IL-2) to the IL-2 receptor (IL-2R) induces rapid increase in tyrosine phosphorylation of cellular substrates through activation of non-receptor protein tyrosine kinases. Here, we report that stimulation through the IL-2R induced tyrosine phosphorylation of the SH2-containing protein-tyrosine phosphatase SHP-2 in F7, a hematopoietic BAF-B03 transfectant clone expressing the IL-2Rbeta chain. The tyrosine phosphorylation of SHP-2 was specific since another protein-tyrosine phosphatase SHP-1, which is structurally homologous to SHP-2, was not tyrosine phosphorylated. The IL-2-induced tyrosine phosphorylation of SHP-2 required the acidic region within the IL-2Rbeta chain where Src-family PTKs interact. Though the serine-rich region within IL-2Rbeta chain was also required for the phosphorylation of SHP-2, Jak3 activation was dispensable. In COS-7 cells, co-expression of SHP-2 with Lyn resulted in increased tyrosine phosphorylation levels of SHP-2, whereas co-expression of SHP-2 with Fyn failed to alter the levels significantly. Considering that Lyn and Fyn are major Src-family PTKs expressed in BAF-B03 cells, our data suggest that Lyn may be principally responsible for the tyrosine phosphorylation of SHP-2 in F7 cells. Furthermore, the IL-2 stimulation also induced tyrosine phosphorylation of SHP-2 in the human IL-2-dependent T-cell line ILT-Mat. Taken together, these studies demonstrate an involvement of SHP-2 in the IL-2-mediated signaling events through the activation of specific PTKs.

A purified protein from Salmonella typhimurium inhibits high-affinity interleukin-2 receptor expression on CTLL-2 cells.

Previously, we have demonstrated that the immunosuppression induced by the purified substance Salmonella typhimurium-derived inhibitor of T-cell proliferation (STI) involves T-cell non-responsiveness to interleukin-2 (IL-2). In the present study, it was found that STI inhibited the growth of CTLL-2 cells, which are an IL-2-dependent cytotoxic T-cell line. Analysis of IL-2 receptor (IL-2R) function showed that STI inhibited high-affinity receptor expression and internalization by CTLL-2 cells. Furthermore, FACS analysis demonstrated that STI inhibited both beta chain and gamma chain expression of IL-2R on the cells. These results suggest that the suppression of T-cell proliferation induced by STI results from a defect in IL-2R function.

Interleukin-15 gene transcripts are present in rejecting islet allografts

I L-2-DEFICIENT mice reject islet allografts in a T-celldependent fashion,’ proving that factors other than IL-2 can participate in rejection. IL-15, a macrophage product, is a recently described cytokine that supports T-cell growth in vitro and whose effects on T-cell proliferation are not blocked by cyclosporine.2.” The IL-15 receptor is a trimolecular complex consisting of a unique alpha chain as well as the beta and gamma chains of the IL-2 receptor.4 Common utilization of the IL-2 receptor beta and gamma chains is responsible for the similar biologic activities of IL-2 and IL-15.4 We hypothesized that IL-15 might participate in T-cell proliferation and rejection in an IL-Zdeficient system. To test this hypothesis we have performed islet allografts in IL-2 (-/-) knock-out (IL-2 KO) and IL-2 (+/+) wild type (IL-2 WT) mice and analyzed the expression of mRNA encoding for IL-15 using quantitative RTPCR.

Absolute dependence of T cell receptor(hi) cell generation and relative dependence of T cell receptor(int) cell generation on the thymus.

Recent evidence indicates that conventional T cells are generated by the mainstream of T cell differentiation in the thymus and acquire a high density of T cell receptor expression (i.e. TCRhi). In contrast, primordial T cells (or NK1.1+ T cells) are generated by the extrathymic pathways or an alternative intrathymic pathway and express an intermediate density of TCR (i.e. TCRint). To obtain further evidence, it was examined how thymus grafting influenced the distribution of T cell populations in athymic nude mice. When BALB/c nu/nu mice were engrafted with thymocyte-depleted BALB/c+/+ fetal thymi, two changes emerged after grafting: nude mice generated TCRhi cells de novo in the periphery as well as in the grafted thymi, and the absolute number of interleukin-2 receptor beta chain+ TCRint cells increased prominently in number in the periphery. Among thymic hormones tested, the administration of thymosin alpha induced a slight expansion of CD3int cells in nude mice. To examine a possible interaction of TCRint cells with TCRhi cells in the periphery, B6 nu/nu mice (Ly5.2+) were injected with TCRhi cells purified from the spleen of B6 Ly5.1 congenic mice. In this case, TCRint (Ly5.2+) cells expanded well in all tested organs of nude mice. These results suggest that the generation of TCRhi cells is absolutely dependent on the thymus and that TCRint cells expand under the influence of the thymus (humoral) and due to interaction with thymus-derived conventional T cells.

Therapeutic effects of glycyrrhizin in mice infected with LP-BM5 murine retrovirus and mechanisms involved in the prevention of disease progression.

Glycyrrhizin (GL), a plant extract, has been evaluated for its inhibitory effect on HIV replication in vitro and for its improvement of clinical symptoms in HIV-infected patients. In this study, we used GL in a murine AIDS model (MAIDS) to evaluate these effects. C57BL/6 mice were inoculated with LP-BM5 murine leukemia virus to cause MAIDS. Treatment with GL supplemented with glycine and cysteine (Stronger Neo-Minophagen C, SNMC) was then begun on day 0 or 4 wks after virus inoculation. SNMC was administered three times a week for up to 19 wks. Immunological abnormalities were monitored with respect to the surface phenotype identified by two-color staining for CD3 and IL-2 receptor beta-chain. All mice infected with the virus alone developed MAIDS and died by 14 wks after infection. The immunopathogenesis was estimated to be an abnormal expansion of intermediate CD3 cells (i.e., extrathymic T cells) as well as other types of lymphocytes. SNMC did not change the total mortality rate. However, some mice that began the treatment on day 0 or 4 wks after infection survived 3 wks longer. Splenomegaly and lymphadenopathy in such mice were suppressed. These mice showed normal phenotypic features and normal responses to Con A. These results suggest that SNMC is effective in some MAIDS mice in preventing the progression of disease. When lymphocytes isolated from the liver, spleen and lymph nodes of diseased mice were cultured in vitro, they showed a spontaneous proliferation. Interestingly, such proliferation was inhibited by addition of liver lymphocytes, but not splenic lymphocytes, obtained from normal or SNMC-treated mice. Since liver lymphocytes contains intermediate CD3 cells with autoreactivity, they may possibly suppress the progression of disease.

Identification and cellular distribution of the rat interleukin-2 receptor beta chain: induction of the IL-2R alpha- beta+ phenotype by major histocompatibility complex class I recognition during T cell development in vivo and by T cell receptor stimulation of CD4+8+ immature thymocytes in vitro.

A mouse monoclonal antibody (mAb) to the rat interleukin-2 receptor beta (IL-2R beta) chain was generated using IL-2R beta cDNA-transfected mouse L929 cells for immunization and differential screening. This antibody, called L316, detects a cell surface protein with an apparent molecular mass of about 80 kDa. In peripheral lymphoid organs of young adult rats, IL-2R beta expression is restricted to T and natural killer (NK) cells, and less than 10% of IL-2R beta+ cells co-express the IL-2R alpha chain. IL-2R beta was detected on all NKRP-1hi (NK-) and NKRP-1lo cells (T-lineage cells of unknown function), most peripheral gama delta T cells and on 30-40 % of CD8 and 10 % of CD4 alpha beta T cells. In the adult rat thymus, mAb L316 detects a small subset (about 1%) of predominantly IL-2R alpha- cells which express cell surface markers characteristic of mature T lymphocytes and contain a high proportion of CD4-8- and CD4-8+ alpha beta T cell receptor (TCR)+ thymocytes. TCR-V usage suggests that major histocompatibility complex (MHC) class I plays a more important role than MHC class II in the selection of these cells. On immature CD4+8+ rat thymocytes, IL-2R beta cell surface expression is readily induced by TCR stimulation in vitro, supporting the idea that in vivo, the IL-2R beta+ phenotype is the the result of TCR engagement during thymic selection.

Analysis of IL-2 receptor expression and of the biological effects of IL-2 gene transfection in small-cell lung cancer.

We have analysed the expression of interleukin-2 receptor (IL-2R) on a panel of small-cell lung cancer (SCLC) cell lines. None of the 11 SCLC cell lines studied expressed detectable surface IL-2R alpha or beta chains by indirect immunofluorescence. Reverse transcriptase-polymerase chain reaction (RT-PCR) analyses indicated that only one out of 11 cell lines expressed detectable IL-2R beta mRNA while two expressed a weak positivity for IL-2R gamma. Five SCLC cell lines were transfected with the plasmid vector RSV.5 neo containing IL-2 cDNA coding sequence. Stable transfectants secreted biologically active IL-2 (ranging from 25 to 100 U ml-1 in the culture supernatant). IL-2 transfection did not produce significant modifications in the expression of surface molecules such as IL-2R alpha and beta chains, intercellular adhesion molecule-1 (ICAM-1), CD44, HLA class I and II or in IL-2R beta or gamma mRNA. More importantly, IL-2-transfected N592 and NCI H69 cell lines completely lost their tumorigenic potential in nude mice after subcutaneous injection, whereas experimental controls transfected with RSV.5 neo vector only, displayed an in vivo growth pattern identical to that of untransfected cells. In addition, in the N592 model, IL-2-producing N592 inhibited the growth of wild-type N592 injected at the same site, while injection of parental cells on the opposite side did not significantly affect the growth of wild-type tumour cells. Histopathological analysis of the rejection process of IL-2-transfected cells demonstrated the presence of MAC-1+, MAC-3+ macrophages and of RB68C5+ granulocytes, whereas T cells were undetectable and NK cells were scarcely represented. In addition, a reduction of the tumour blood vessels was observed. The possible relevance of these data for the development of vaccination strategies using cytokine-engineered tumour cells in SCLC is discussed.

Increased mucosal concentrations of soluble intercellular adhesion molecule-1 (sICAM-1), sE-selectin, and interleukin-8 in active ulcerative colitis.

Cell surface adhesion molecules (CAM) are important promotors of the immunoinflammatory cascade. The circulating levels of soluble intercellular adhesion molecule 1 (ICAM-1) have previously been shown to correlate with disease activity in inflammatory bowel disease. The primary aim of this study was consequently to investigate if this also applies to mucosal levels of soluble ICAM-1. We measured soluble ICAM-1 levels in intestinal biopsy specimens and the endoscopic activity of 69 patients with ulcerative colitis (UC) and 14 controls and found that the median concentration of soluble ICAM-1 was significantly higher in patients with moderately or very active UC (15.0 ng/ml) as compared to slightly active (9.8 ng/ml) and inactive UC (9.5 ng/ml) as well as controls (6.5 ng/ml) (P < 0.005). To further elucidate the interactions, two other CAM [E-selectin and vascular cellular adhesion molecule 1 (VCAM-1)], together with interleukin-8 (IL-8), IL-2 receptor (IL-2R) alpha and beta chains, were also measured. A significant trend towards higher soluble E-selectin levels in biopsies with active UC (1.8 pg/ml) as compared to inactive UC (1.3 pg/ml) and to controls (< 1.0 pg/ml) (P < 0.01) was also found. In contrast, soluble VCAM-1 was barely detectable in biopsies from two UC patients. A significant correlation was found between soluble ICAM-1 and IL-8 concentrations (r = 0.46; P < 0.0001), and between sICAM-1 and sIL-2R alpha concentrations (r = 0.69; P < 0.0001), while sIL-2R beta was not detected. This study shows that intestinal ICAM-1 and E-selectin correlate with endoscopic activity of UC and with IL-8 and IL-2R alpha levels. These mediators may be useful in monitoring mucosal inflammation in studies exploring the therapeutical potential of targeting CAM. The lack of detectable VCAM-1, which is induced only in venous endothelium is interesting. It may suggest that intestinal inflammation mainly affects arterial endothelial cells and support the theory that intestinal vasculitis is involved in the pathogenesis of inflammatory bowel disease.

Expression of IL-2R, IL-4R, IL-6R on peripheral blood lymphocytes in systemic lupus erythematosus and correlation with disease activity: a prospective study.

To study the expression of interleukin-2 receptor (IL-2R), interleukin-4 receptor (IL-4R) and interleukin-6 receptor (IL-6R) on peripheral blood lymphocytes (PBL) in patients with systemic lupus erythematosus (SLE); to correlate the level of expression of these receptors with SLE disease activity. Peripheral blood lymphocytes were studied by a high sensitivity flow cytometry technique using monoclonal antibodies directed against CD25 (IL-2R alpha chain), CD122 (IL-2R beta chain), CD124 (IL-4R), and CD126 (IL-6R). SLE disease activity was scored using the SLE Disease Activity Index, C3 and C4 concentrations, anti-dsDNA level, and absolute lymphocyte count. Compared with normal controls, PBL from patients with SLE had a higher percentage of CD25+ cells (median 20.8% v 16.5%) and a lower percentage of CD122+ cells (median 13.1% v 22.4%). The difference in CD122+ cells was greater in the CD122weak population than the CD122strong (natural killer cell) population. The percentages of CD124+ and CD126+ PBLs in patients with SLE and controls were similar. On CD25+ cells, the relative antigenic level of the IL-2R alpha chain was significantly higher in patients with SLE (median 2.01 v 1.81). The relative antigenic levels of CD122+, CD124+ and CD126+ cells were similar in patients and controls. Neither the percentages nor the relative antigenic levels of all of these cytokine receptors were correlated with any of the parameters of disease activity. Lymphocyte activation in patients with SLE was evident from the increase in CD25 expression on PBL, with a reciprocal decrease in CD122 expression. As the expression of IL-2R, IL-4R, IL-6R did not correlate with disease activity, it seems that these cytokine/receptor systems do not play a direct role in disease activation in SLE.