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1.
We have investigated the association of the recently identified IL6R polymorphisms with the serum levels of soluble IL-6 receptor (sIL-6R). sIL-6R is generated by shedding of the membrane-bound receptor (IL-6Ralpha) or alternative mRNA splicing. In total, 115 healthy volunteers were genotyped, with 70 of them analyzed for sIL-6R levels. Using the PCR/RFLP methods, two important polymorphic sites were selected for genotyping: the 48892A/C (D358A) in exon 9 and the -183G/A in the promoter region. In exon 9, C allele carriers had higher sIL-6R level (P<0.0001) showing that this sequence variation, which corresponds to the proteolytic cleavage site of IL-6Ralpha, strongly influences the serum sIL-6R levels. In the promoter region, G allele carriers had lower sIL-6R levels (P<0.0082) compared with the A allele carriers. This could be attributed to the linkage disequilibrium (D'=0.54, chi2=51.3, P<0.0001) between the -183G/A and the 48892A/C gene polymorphisms.  相似文献   

2.
3.
Interleukin-6 (IL-6) binds to a receptor complex consisting of an 80 kDa binding unit (IL-6R) and gp130 responsible for signal transduction. Due to alternative splicing and/or proteolytic digestion IL-6R occurs in soluble form (sIL-6R), as well. Soluble IL-6R is able to bind to gp130 expressing on nucleated cells, thus sIL-6R makes most cells responsive to IL-6. In this study we found that oncostatin M (OSM), an other gp130 dependent cytokine with proliferation inhibitory potential, increases the expression of both membrane-bound IL-6R and sIL-6R generated by alternative splicing in hepatic and mammary carcinoma cell lines. Furthermore, we studied the functional relevance of the presence and binding of soluble IL-6R to HepG2 cells. Using a cDNA expression array, mRNA levels of about 580 human genes were tested by differential display analysis. Our findings suggest, that elevation of surface density of IL-6R by attachment of sIL-6R induces major modulation in gene expression profile of the hepatoma cells. Soluble IL-6R alone has minor effect, it rather decreases expression of some genes, while incubation with IL-6 and sIL-6R together induces major changes in the mRNA pattern of HepG2 cells. These data strongly suggest that presence and binding of soluble cytokine receptors are important elements of inter-cytokine cross talk and affects actual gene expression profile of responding cells.  相似文献   

4.
IL-6 transsignaling: the in vivo consequences.   总被引:8,自引:0,他引:8  
Cytokine receptors exist in membrane-bound and soluble forms. They bind their ligands with comparable affinity. Although most soluble receptors are antagonists because they compete with their membrane counterparts for their ligands, some soluble receptors are agonists. In this case, on target cells, the complex of cytokine and soluble cytokine receptor binds to a second receptor subunit and initiates intracellular signal transduction. The soluble receptors of the interleukin-6 (IL-6) family of cytokines--soluble IL-6 receptor (sIL-6R), sIL-11R, and soluble ciliary neurotrophic factor receptor (sCNTFR)--are agonists. In vivo, the IL-6/sIL-6R complex stimulates several types of target cells not stimulated by IL-6 alone, as they do not express the membrane- bound IL-6R. This process has been named transsignaling. We have shown recently that in several chronic inflammatory diseases, such as chronic inflammatory bowl disease, peritonitis, and rheumatoid arthritis, as well as in colon cancer, transsignaling via the sIL-6R complexed to IL-6 is a crucial point in the maintenance of the disease. The mechanism by which the IL-6/sIL-6R complex regulates the inflammatory or neoplastic state is discussed.  相似文献   

5.
A number of investigators has reported that there is increased production of interleukin-6 (IL-6) by fibroblasts and monocytes from the patients with systemic sclerosis (SS). However, the precise role of IL-6 in the pathogenesis of SS remains unclear. On the basis of our previous study showing that the complex of IL-6 and soluble IL-6 receptor (sIL-6R) could induce synovial fibroblast proliferation, we examined whether the IL-6-s1L-6R complex could induce the proliferation of normal dermal fibroblastic cells (DF). IL-6 suppressed DF proliferation, and, in the presence of sIL-6R, dose-dependently showed much stronger suppressive effects on DF proliferation. This suppression was completely blocked by either anti-IL-6 or anti-sIL-6R antibody. Furthermore, the IL-6-sIL-6R complex significantly suppressed IL-1β-, TNFα- and PDGF-AA-induced DF proliferation. These lines of evidence suggest that the IL-6-sIL-6R complex may have potential as a useful agent for the treatment of SS.  相似文献   

6.
Interleukin-6 (IL-6) is hypothesized to play an important role in the interaction between immune mechanisms and the central nervous system. We investigated whether cerebrospinal fluid (CSF) concentrations of interleukin-6 (IL-6), the soluble IL-6 receptor (sIL-6R) and the soluble form of the signal transducing and affinity converting receptor gp130 (sgp130) are altered in geriatric patients with major depression (MD). In 20 geriatric patients with MD and 20 age-matched healthy control subjects CSF concentrations of the three components of the sIL-6R complex were analyzed by enzyme-linked immunosorbent assays (ELISA). All patients except one were treated with psychotropic drugs. We found statistically significant decreased CSF concentrations of IL-6 (P<0.001) and of the sIL-6R (P<0.001) of patients with MD. Levels of sgp130 showed no statistically significant difference between patients and controls.  相似文献   

7.
We measured soluble IL-6 receptor (sIL-6R) levels in serum and bronchoalveolar lavage fluids (BALF) from patients with interstitial pneumonia of unknown etiology (IP) (n = 17), sarcoidosis (n = 8) and normal control subjects (n = 10), to investigate its role in pulmonary diseases. Soluble IL-6R was determined by an ELISA. The volume of epithelial lining fluid (ELF) in BALF was estimated using an urea method. We found that levels of sIL-6R in serum, BALF, and ELF from patients with IP or sarcoidosis were significantly higher than those from normal subjects. Furthermore, levels of sIL-6R in BALF or ELF were significantly correlated with those of albumin, indicating that sIL-6R, together with albumin, may enter ELF as a result of the increased permeability caused by pulmonary inflammation. Thus most of the sIL-6R in ELF would be from serum, and relatively small amounts of it might be produced locally. However, sIL-6R levels in ELF, but neither serum nor BALF, were significantly correlated with levels of C-reactive protein in patients with IP. These results suggest that both systemic and local production of sIL-6R are increased, and raised sIL-6R is involved in the modulation of systemic and local inflammatory responses in patients with IP and sarcoidosis.  相似文献   

8.
9.
The soluble IL-6 receptor (sIL-6R) is generated through either proteolytic shedding of the cognate receptor (PC-sIL-6R), or released as the product of differential mRNA splicing (DS-sIL-6R). Using monocytic THP-1 cells, we demonstrate that both mechanisms are independently regulated, and that each process contributes to sIL-6R production. Shedding of the IL-6R was activated by the Ca2+ ionophore, ionomycin, and inhibited by the TNF-α protease inhibitor (TAPI). In contrast, basal sIL-6R release was unaffected by Ca2+ depletion and largely insensitive to TAPI. Moreover, although IL-6R shedding was inactivated by serum starvation, non-stimulated production remained intact. Basal sIL-6R production via differential mRNA splicing was shown through the inhibitory action of brefeldin A and an enzyme-linked immunosorbent assay specific for DS-sIL-6R. Release of this isoform was unaffected by ionomycin or TAPI, indicating that Ca2+ mobilization activates PC-sIL-6R generation, but not DS-sIL-6R. The divergent control of these sIL-6R isoforms indicates that they may independently influence the inflammatory response.  相似文献   

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11.
We have previously shown, using human T-cell lymphocytotrophic virus-I (HTLV-I)-infected cell lines, that soluble interleukin-6 receptor (sIL-6R) is generated through an alternative splicing mechanism. In this study, we examined human sera for the presence of alternatively spliced soluble IL-6R (AS-sIL-6R). We produced a monoclonal antibody (mAb) recognizing the unique sequence of AS-sIL-6R peptide, generated by an altered reading frame. We also made recombinant AS-sIL-6R protein in Spodoptera frugiperda-9 (Sf-9) cells carrying baculovirus, which encoded altered sIL-6R or conventional IL-6R cDNA. mAbs specifically recognized AS-sIL-6R, but not conventional IL-6R, as demonstrated by Western blot analyses, fluorescence-activated cell sorter, immunofluorescence analyses and enzyme-linked immunosorbent assay (ELISA). We adapted an ELISA system and used it for detection of altered sIL-6R in sera from 23 healthy persons, 12 patients with adult T-cell leukaemia (ATL) and 13 patients with HTLV-I-associated myelopathy (HAM). Serum levels of AS-sIL-6R were 6.4 or 6.1 times greater in ATL (28.7+/-20.4 ng/ml, P<0.0001) and in HAM patients (27.5+/-12.1 ng/ml, P<0.0001) than in healthy individuals (4.5+/-2.1 ng/ml). High levels of AS-sIL-6R were also observed in plasma from rheumatoid arthritis patients and in persons with elevated levels of alanine aminotransferase (ALT), antinuclear antibody (ANA), or alpha-fetoprotein (AFP). However, in human immunodeficiency virus-1 (HIV-1), hepatitis B virus (HBV) or hepatitis C virus (HCV)-infected individuals, AS-sIL-6R levels were not elevated. In this study, we confirmed that AS-sIL-6R is indeed present in human sera. These observations suggest that alternative splicing of IL-6R mRNA is of consequence in ATL, HAM and in some autoimmune diseases. The HTLV-I-infected T cells appeared to play an important role in AS-sIL-6R production.  相似文献   

12.
Influenza A virus (IAV) infection is a major worldwide public health problem. However, the factors involved in mediating the inflammatory response to this infection and their relationships remain poorly understood. Here, we show that IAV infection stimulates the expression of the soluble IL-6 receptor (sIL-6R), a multifunctional protein involved in IL-6 signaling. Interestingly, sIL-6R expression upregulated the levels of its own ligand, IL-6 and those of the pro-inflammatory cytokine IL-32. shRNA-mediated knockdown of sIL-6R suppressed IL-6 and IL-32, indicating that this regulation is dependent on sIL-6R during IAV infection. Furthermore, our results demonstrate that IL-32 participates in a negative feedback loop that inhibits sIL-6R while upregulating IL-6 expression during IAV infection. Therefore, we show that sIL-6R is a critical cellular factor involved in the acute inflammatory response to viral infection.  相似文献   

13.
BACKGROUND: The effects of cytokines are modulated by soluble cytokine receptors (SCR) and receptor antagonists. Therefore, allergic disease may depend on altered proportions between cytokines, their SCR and receptor antagonists, rather than absolute changes in cytokine levels. Little is known about SCR in intermittent allergic rhinitis (IAR). OBJECTIVE: To examine the concentrations of SCR, i.e. sIL-1R2, sIL-4R, sIL-6R and sTNFR1, as well as the interleukin-1 receptor antagonist (IL-1Ra) in nasal fluids from allergen-challenged patients with IAR and healthy controls. METHODS: 30 patients with birch- or grass-pollen-induced IAR and 30 healthy controls were studied. In the patients nasal fluids were obtained before as well as 1 and 6 h after allergen provocation. RESULTS: Both symptom scores and rhinoscopic signs of rhinitis increased in the patients after allergen challenge. Comparisons between patients and controls showed that sIL-4R was lower in patients before and 1 and 6 h after provocation. IL-1Ra was lower before and 1 h after provocation. In addition, lower concentrations of sTNFR1 were found in patients after 1 h, while sIL-1R2 concentrations were higher after 1 h. Comparisons of patients before and after challenge showed that IL-1Ra and sTNFR1 decreased after 1 h, while sIL-1R2 increased. No significant differences were found compared to 6 h. sIL-6R did not significantly differ between the study groups. CONCLUSIONS: After allergen challenge, significant changes in the nasal fluid levels of IL-1Ra, sIL-1R2 and sTNFR1 were found. By contrast, sIL-4R remained at lower levels than in controls both before and after challenge. Since sIL-4R modulates IgE synthesis, this may play a role in the pathogenesis of IAR.  相似文献   

14.
Cytokine receptors, which exist in membrane-bound and soluble forms, bind their ligands with comparable affinity. Although most soluble receptors are antagonists and compete with their membrane-associated counterparts for the ligands, certain soluble receptors are agonists. In these cases, complexes of ligand and soluble receptor bind on target cells to second receptor subunits and initiate intracellular signaling. The soluble receptors of the interleukin (IL)-6 family of cytokines (sIL-6R, sIL-11R, soluble ciliary neurotrophic factor receptor) are agonists capable of transmitting signals through interaction with the universal signal-transducing receptor for all IL-6 family cytokines, gp130. In vivo, the IL-6/sIL-6R complex stimulates several types of cells, which are unresponsive to IL-6 alone, as they do not express the membrane IL-6R. We have named this process trans-signaling. The generation of soluble cytokine receptors occurs via two distinct mechanisms-limited proteolysis and translation-from differentially spliced mRNA. We have demonstrated that a soluble form of the IL-6 family signaling receptor subunit gp130, which is generated by differential splicing, is the natural inhibitor of IL-6 trans-signaling responses. We have shown that in many chronic inflammatory diseases, including chronic inflammatory bowel disease, peritonitis, rheumatoid arthritis, asthma, as well as colon cancer, IL-6 trans-signaling is critically involved in the maintenance of a disease state, by promoting transition from acute to chronic inflammation. Moreover, in all these models, the course of the disease can be disrupted by specifically interfering with IL-6 trans-signaling using the soluble gp130 protein. The pathophysiological mechanisms by which the IL-6/sIL-6R complex regulates the inflammatory state are discussed.  相似文献   

15.
This study was designed to investigate the effects of a combination of soluble interleukin (sIL)-6 receptor (R) and IL-6 on the ex vivo expansion of human peripheral blood (PB)-derived hematopoietic progenitor cells in a short-term serum-free liquid suspension culture system, using PB-derived CD34(+)IL-6R(+/-) cells as a target. In combination with stem cell factor (SCF), IL-3, and sIL-6R/IL-6, the expansion efficiency (EE) for granulocyte/macrophage colony-forming unit (CFU-GM) reached a peak level on day 10 of incubation. On the other hand, the EE for erythroid burst (BFU-E) and mixed colony-forming unit (CFU-Mix) reached a peak level on day 7 of incubation. Among the cytokine combinations tested, SCF + IL-3 + sIL-6R/IL-6 + flt3 ligand (FL) most effectively expanded CFU-GM and CFU-Mix. The maximum EEs for CFU-GM and CFU-Mix were 208-fold and 42-fold, respectively. While the EE for BFU-E was 70-90-fold in the presence of SCF + IL-3 + sIL-6R/IL-6, FL significantly augmented the EE for CFU-GM and CFU-Mix. In contrast, thrombopoietin (TPO) significantly augmented the EE for CFU-Mix. Interestingly, in combination with IL-3 and SCF, newly generated IL-6R/IL-6 fusion protein (FP) expanded PB-derived BFU-E and CFU-Mix twice more effectively than a combination of sIL-6R and IL-6. These results demonstrated that human PB-derived committed progenitors were effectively expanded in vitro using sIL-6R/IL-6 or FP, in combination with IL-3, SCF and/or FL or TPO, and that FP may transduce a stronger intracellular signal than a combination of sIL-6R and IL-6.  相似文献   

16.
Cytokines interact not only with membrane anchored receptors, but also with specific soluble receptors which circulate in the bloodstream. In general, soluble cytokine receptors such as soluble tumor necrosis factor receptor, soluble interleukin 1 receptor, and soluble interleukin 4 receptor compete with their membrane-bound counterparts for the ligands and therefore act as antagonists. In contrast, soluble receptors for cytokines of the interleukin-6 (IL-6) family complex with their ligands act agonistically. Interestingly, the complex of IL-6 and the soluble interleukin 6 receptor (sIL-6R) activates target cells that do not express the membrane-bound IL-6R and therefore cannot respond to IL-6. To identify cellular responses that are due to IL-6/sIL-6R but not to IL-6 alone, IL-6/sIL-6R double-transgenic mice were generated and compared with IL-6 single-transgenic mice. IL-6/sIL-6R transgenic mice develop a severe phenotype showing 1) marked hepatocellular hyperplasia frequently surrounded by peliosis and necrosis, 2) significant acceleration and aggravation of plasmacytoma formation, and 3) excessive activation of extramedullary hematopoiesis in spleen and liver followed by a subsequent increase of all cellular components in the peripheral blood. These in vivo data suggest that the sIL-6R recruits primarily unresponsive cell populations such as hematopoietic progenitor cells and hepatocytes to IL-6-induced proliferation, but also enhances the known mitogenic effect of IL-6 on plasma cells and thereby contributes to plasmacytoma formation.  相似文献   

17.
IL-6 acts on target cells via the ligand-binding protein interleukin-6 receptor (IL-6R) and the affinity-converting and signal-transducing glycoprotein 130 (gp130). Soluble interleukin-6 receptor (sIL-6R) has an agonistic role because the soluble complex (IL-6/sIL-6R) can activate cells that do not express IL-6R and an antagonistic role as it enhances the inhibitory activity of sgp130. Soluble forms of both receptors, sIL-6R and sgp130, regulate the action of IL-6. sIL-6R was measured by a sensitive enzyme-linked immunosorbent assay in paired sera and cerebrospinal fluid (CSF) from 46 patients with inflammatory neurological diseases (IND), 45 patients with relapsing-remitting multiple sclerosis (RR-MS), 13 patients with primary progressive multiple sclerosis (PP-MS), 17 patients with other non inflammatory neurological diseases (NIND) and 13 mentally healthy individuals--healthy controls (HC). Patients with RR-MS had CSF sIL-6R levels comparable to those from patients with IND, but higher than patients with NIND and HC. A positive correlation between the CSF/serum albumin (QAlb) and CSF sIL-6R levels was observed in IND but not in RR-MS patients indicating that CSF sIL-6R levels in IND patients could be influenced by serum sIL-6R and blood brain barrier (BBB) permeability properties. RR-MS patients had higher values of [CSF/serum sIL-6R:CSF/serum albumin] (sIL-6R index) than IND patients suggesting that in multiple sclerosis (MS), the increase in CSF sIL-6R could be due to intrathecal synthesis of sIL-6R. The finding of increased CSF sIL-6R concentrations (>979 pg/ml) with sIL-6R index (>4.66), in correlation with positive oligoclonal bands in RR-MS patients, suggests that values of sIL-6R index > 4.66 indicate intrathecal increase of sIL-6R and might be used as an indicator of neuroimmunoregulatory and inflammatory processes in the central nervous system (CNS).  相似文献   

18.
IL-6, soluble IL-6 receptor (sIL-6R) and soluble gp130 (sgp130) levels were measured in sera and pleural effusions from 42 patients with metastatic carcinoma, non-Hodgkin's lymphoma, tuberculosis, cardiac failure and miscellaneous diseases. Pleural IL-6 levels measured by ELISA were very high in all patient groups (mean 34.8 ± 15.3 ng/ml) without significant difference according to diseases. IL-6 was shown to be biologically active in a proliferative assay. Serum IL-6 levels were low (0.049 ± 0.014 ng/ml) and did not correlate with pleural fluid levels. Pleural IL-6 levels correlated with the number of polymorphonuclear cells in pleural fluid (P< 0.03). Pleural sIL-6R levels (76 ± 8 ng/ml) were always lower than serum levels (196 ± 12 ng/ml; P< 0.0001) but correlated with them (P< 0.01). Pleural sIL-6R and albumin levels correlated (P< 0.01), suggesting a transudation of sIL-6R from the serum. Pleural sgp130 levels (10.9 ± 1.0 ng/ml) were lower than serum levels (24.6 ± 2.8 ng/ml; P< 0.002). After gel filtration of pleural fluid, the bulk of IL-6 (>90%) was recovered in a 15 000–30 000 fraction, corresponding to the expected mol. wt of free IL-6. These results suggest a production and a sequestration of IL-6 in the pleural cavity in all studied conditions.  相似文献   

19.
The undisturbed development of the enteric nervous system depends on the supply of various neurotrophic factors during ontogenesis. Besides glial cell line-derived neurotrophic factor (GDNF), leukemia inhibitory factor (LIF) and ciliary neurotrophic factor (CNTF) take part in its development. CNTF and LIF belong to the interleukin-6 (IL-6) family of cytokines. The combination of IL-6 and the soluble IL-6 receptor accelerates peripheral nerve regeneration. In this study, we examined the effect of the fusion protein Hyper-IL-6, which consists of IL-6 and the soluble receptor sIL-6R, on neurite outgrowth and neuronal survival in vitro. Myenteric plexus of newborn rats was dissected and dissociated. Cells were grown in either serum-free chemically defined medium alone or medium supplemented with sIL-6R, IL-6, sIL-6+IL-6, Hyper-IL-6, CNTF, LIF, or GDNF. Average neurite outgrowth per neuron was highest in GDNF-treated and Hyper-IL-6-treated cultures. The number of neurite-bearing neurons was reduced in GDNF cultures compared with Hyper-IL-6-treated cells, so that the total neurite outgrowth was maximal after Hyper-IL-6 stimulation. Hyper-IL-6 furthermore stimulated neuronal survival and morphologic differentiation of the enteric glia.  相似文献   

20.
Interleukin 10 (IL-10) is a dimeric cytokine that plays a central role in suppressing inflammatory responses. These activities are dependent on the interaction of IL-10 with its high-affinity receptor (IL-10R1). This intermediate complex must subsequently recruit the low-affinity IL-10R2 chain before cell signaling can occur. Here we report the 2.9 A crystal structure of IL-10 bound to a soluble form of IL-10R1 (sIL-10R1). The complex consists of two IL-10s and four sIL-10R1 molecules. Several residues in the IL-10/sIL-10R1 interface are conserved in all IL-10 homologs and their receptors. The data suggests that formation of the active IL-10 signaling complex occurs by a novel molecular recognition paradigm where IL-10R1 and IL-10R2 both recognize the same binding site on IL-10.  相似文献   

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