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Direct adenovirus-mediated gene transfer of interleukin 1 and tumor necrosis factor α soluble receptors to rabbit knees with experimental arthritis has local and distal anti-arthritic effects

Ghivizzani, Steven C.; Lechman, Eric R.; Kang, Richard; Tio, Caroline; Kolls, Jay; Evans, Christopher H.; Robbins, Paul D.
Fonte: The National Academy of Sciences Publicador: The National Academy of Sciences
Tipo: Artigo de Revista Científica
Publicado em 14/04/1998 Português
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55.67%
Adenoviral vectors were used to deliver genes encoding a soluble interleukin 1 (IL-1)-type I receptor-IgG fusion protein and/or a soluble type I tumor necrosis factor α (TNFα) receptor-IgG fusion protein directly to the knees of rabbits with antigen-induced arthritis. When tested individually, knees receiving the soluble IL-1 receptor had significantly reduced cartilage matrix degradation and white blood cell infiltration into the joint space. Delivery of the soluble TNFα receptor was less effective, having only a moderate effect on white blood cell infiltration and no effect on cartilage breakdown. When both soluble receptors were used together, there was a greater inhibition of white blood cell infiltration and cartilage breakdown with a considerable reduction of synovitis. Interestingly, anti-arthritic effects were also seen in contralateral control knees receiving only a marker gene, suggesting that sustained local inhibition of disease activity in one joint may confer an anti-arthritic effect on other joints. These results suggest that local intra-articular gene transfer could be used to treat systemic polyarticular arthritides.

Interleukin 1 signaling occurs exclusively via the type I receptor.

Sims, J E; Gayle, M A; Slack, J L; Alderson, M R; Bird, T A; Giri, J G; Colotta, F; Re, F; Mantovani, A; Shanebeck, K
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em 01/07/1993 Português
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55.8%
Two receptors for the proinflammatory cytokine interleukin 1 (IL-1) have been cloned and characterized biochemically. While it has been well established that the type I (80-kDa) IL-1 receptor can mediate responses to IL-1, the function of the type II (60-kDa) IL-1 receptor has been unknown. In this manuscript we describe experiments designed to ask whether the type II receptor is capable of delivering a biological signal. We have examined two types of experimental situation: responses to IL-1 in cells which express predominantly the type II receptor, and responses to IL-1 which have been suggested previously in the literature to be mediated by type II receptors. In both situations we find that the responses instead are mediated via type I receptors. A blocking antibody against the type II receptor never inhibits, and in fact sometimes enhances, the responses. We conclude that a very small number of type I receptors is sufficient to mediate all of the actions of IL-1 which we have examined here and that the function of the type II receptor may not be to transduce signals.

Identification of the discontinuous binding site in human interleukin 1 beta for the type I interleukin 1 receptor.

Labriola-Tompkins, E; Chandran, C; Kaffka, K L; Biondi, D; Graves, B J; Hatada, M; Madison, V S; Karas, J; Kilian, P L; Ju, G
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em 15/12/1991 Português
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45.74%
Human interleukin 1 beta (IL-1 beta) exerts its diverse biological effects by binding to specific receptors on target cells. Two types of IL-1 receptor (IL-1R) have been identified: the type I IL-1R (p80) and the type II IL-1R (p68). Using site-specific mutagenesis, we have identified the binding site on IL-1 beta for the murine type I IL-1R. Analogs of the IL-1 beta protein containing defined amino acid substitutions were produced and tested for competitive binding to the two IL-1Rs. Substitutions of the amino acids at seven positions resulted in analogs that had greater than or equal to 100-fold reductions in competitive binding to the type I IL-1R, while maintaining substantial binding to the type II IL-1R. These seven amino acids (Arg-4, Leu-6, Phe-46, Ile-56, Lys-93, Lys-103, and Glu-105) are clustered in the IL-1 beta molecule, forming a discontinuous binding site. The side chains of all seven residues are exposed on the surface of IL-1 beta. The cumulative binding energies contributed by each of the residues predict a binding affinity that is consistent with the observed Kd of the wild-type protein for the type I IL-1R.

Down-regulation of gamma interferon, tumor necrosis factor type I, interleukin 1 (IL-1) type I, IL-3, IL-4, and transforming growth factor beta type I receptors at the local site during the acute phase of Shigella infection.

Raqib, R; Lindberg, A A; Björk, L; Bardhan, P K; Wretlind, B; Andersson, U; Andersson, J
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /08/1995 Português
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55.82%
An immunohistochemical technique was used to examine whether there was a colocalization of cytokine-specific receptors with cytokine-expressing cells. We have previously shown that there is extensive cytokine production and secretion in the rectal mucosa in shigellosis (interleukin 1 alpha [IL-1 alpha], IL-1 beta, IL-1ra, IL-4, IL-6, IL-8, IL-10, tumor necrosis factor alpha [TNF-alpha], TNF-beta, gamma interferon, granulocyte-macrophage colony-stimulating factor, and transforming growth factor beta [TGF-beta]) (R. Raqib, A. A. Lindberg, B. Wretlind, P. K. Bardhan, U. Andersson, and J. Andersson, Infect. Immun. 63:289-296, 1995; R. Raqib, B. Wretlind, J. Andersson, and A. A. Lindberg, J. Infect. Dis. 171:376-384, 1995). Kinetics for receptor expression was compared with that for cytokine synthesis in the inflamed rectal mucosa from Shigella-infected patients during acute (2 to 6 days after onset of diarrhea) and convalescent (30 to 40 days after onset) stages. Quantification of receptor expression was assessed by computer-assisted analysis of video microscopic images. A selective down-regulation of the receptors for gamma interferon, tumor necrosis factor (TNF receptor [TNFR] type I), IL-1 (IL-1 receptor [IL-1R] types I and type II)...

Interleukin 1-induced calcium signalling in chondrocytes requires focal adhesions.

Luo, L; Cruz, T; McCulloch, C
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em 01/06/1997 Português
Relevância na Pesquisa
45.71%
The cytokine interleukin 1 (IL-1) is an important mediator of connective-tissue destruction in arthritic joints but the mechanisms by which IL-1 mediates signal transduction in chondrocytes is poorly understood. Previous results have indicated that IL-1 receptors co-localize with focal adhesions [Qwarnstrom, Page, Gillis and Dower (1988) J. Biol. Chem. 263, 8261-8269], discrete adhesive domains of cells that function in cell attachment and possibly in signal transduction. We have determined whether focal adhesions restrict IL-1-induced Ca2+ signalling in primary cultures of bovine chondrocytes. In cells grown for 24 h on fibronectin, the basal intracellular Ca2+ ion concentration ([Ca2+]i) was 100+/-3 nM. Optimal increases of [Ca2+]i above baseline were induced by 10 nM IL-1 (183+/-30 nM above baseline). There was no significant difference between cells plated on fibronectin or type II collagen (P>0.2; 233+/-90 nM above baseline). Ca2+ transients were significantly decreased by the inclusion of 0.5 mM EGTA in the bathing buffer (74+/-11 nM above baseline), and 1 microM thapsigargin completely blocked Ca2+ transients. Cells plated on poly-(l-lysine) or suspended cells showed no Ca2+ increases, whereas cells grown on fibronectin exhibited IL-1-induced Ca2+ responses that corresponded temporally to the time-dependent cell spreading after plating on fibronectin. Cells plated on poly-(l-lysine) and incubated with fibronectin-coated beads exhibited vinculin staining in association with the beads. In identical cell preparations...

Direct secretory effect of interleukin-1 via type I receptors in human colonic mucous epithelial cells (HT29-C1.16E).

Jarry, A; Vallette, G; Branka, J E; Laboisse, C
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /02/1996 Português
Relevância na Pesquisa
55.79%
The stable differentiated human colonic epithelial cell line, HT29-C1.16E, was used to study the effects of interleukin-1 (IL-1) on mucin exocytosis. The main findings include: (a) IL-1 stimulated a rapid release of mucin from filter grown HT29-C1.16E cells, this effect being dose related; (b) this secretory effect was abolished in the presence of the blocking monoclonal antibody M4 specific for IL-1 receptors type I, showing that IL-1 receptors type I mediated IL-1 action; (c) experiments based on chamber cultures showed that these receptors were located on the basolateral membranes of HT29-C1.16E cells; (d) finally, mRNA for IL-1 receptors type I were detected by reverse transcriptase-polymerase chain reaction in these cells. To extend these findings to the in vivo situation, the rapid stimulatory effect of IL-1 on mucin exocytosis may contribute to the wash out of noxious agents during mucosal inflammation.

Interleukin-1 down-regulates gene and surface expression of interleukin-1 receptor type I by destabilizing its mRNA whereas interleukin-2 increases its expression.

Ye, K; Koch, K C; Clark, B D; Dinarello, C A
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /03/1992 Português
Relevância na Pesquisa
45.71%
The interleukin-1 receptor type I (IL-1RtI) plays an important role in the biological effects of IL-1, but regulation of its surface and gene expression remains unknown. We found that occupancy of 2-15% of the IL-1 surface receptor results in dramatic down-regulation of IL-1RtI both at the mRNA and cell surface level in murine D10S cells, a subline of T-helper type 2 cells. At these low occupancy levels (3 x 10(-12) to 3 x 10(-13) M), the reduction in IL-1RtI surface expression appears at 24 hr and continues to 48 and 72 hr. At the mRNA level, low occupancy of the IL-1R results in decreased IL-1RtI mRNA stability; steady state half-life of the IL-1RtI mRNA is reduced from 6 to 1 hr after exposure to 3 x 10(-12) M IL-1. This down-regulation of IL-1RtI by IL-1 is blocked by cycloheximide, suggesting de novo protein synthesis is necessary for decreased RNA stability. Low concentrations of human IL-1 beta, murine and rabbit IL-1 alpha or beta similarly down-regulated IL-1RtI, whereas low concentrations of human IL-1 alpha failed to reduce the receptor surface expression, despite inducing a full proliferative response. We also observed that the effect of IL-1 on this down-regulation was not through protein kinase C (PKC), since PMA rapidly increased IL-1RtI mRNA levels within 30 min and persisted for 24 hr. IL-2 up-regulated IL-1RtI in D10S cells at both mRNA and protein levels. These results demonstrate that low occupancy of IL-1 receptors induces down-regulation of IL-1RtI surface as well as mRNA expression. The regulation of IL-1RtI gene expression may be one of the mechanisms by which IL-1-mediated events are controlled.

Interleukin 1 modulates growth of human renal carcinoma cells in vitro.

Koch, I.; Depenbrock, H.; Danhauser-Riedl, S.; Rastetter, J. W.; Hanauske, A. R.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /04/1995 Português
Relevância na Pesquisa
65.76%
We have investigated the influence of interleukin 1 (IL-1) on growth of human renal carcinoma cells in vitro. Using a capillary soft-agar cloning system, 18% of freshly explanted renal carcinomas were stimulated to grow by IL-1 and 4% were inhibited. Subsequent experiments with established renal cancer cell lines demonstrated that two out of four cell lines (Caki-2, A-498) were sensitive to IL-1. [3H]Thymidine incorporation as well as monolayer growth was enhanced in Caki-2 cells in the presence of high (10%) and low (1%) serum concentrations. Although clonogenic growth of A-498 cells was stimulated by IL-1, overall [3H]thymidine incorporation and monolayer proliferation were decreased. Using radioligand experiments, 250 cell-surface receptors of high affinity (KD 4.5 x 10(-11) M) and 2500 receptors of low affinity (KD 1.3 x 10(-9) M) were detected on A-498 cells. IL-1 binding was reduced under the influence of IL-1. Competition experiments with inhibiting antibodies against IL-1 receptor type I and type II revealed that signal transduction was performed via type I receptors. After cross-linking to IL-1, receptor type I was immunoprecipitated using anti-IL-1 antibodies. We hypothesise that, since IL-1 modulates in vitro growth of a subgroup of human renal cancer cells...

Chemoattractants induce rapid release of the interleukin 1 type II decoy receptor in human polymorphonuclear cells

Fonte: The Rockefeller University Press Publicador: The Rockefeller University Press
Tipo: Artigo de Revista Científica
Publicado em 01/06/1995 Português
Relevância na Pesquisa
55.69%
Molecules representative of different classes of chemotactic agents, including formyl-Met-Leu-Phe (FMLP), C5a, leukotriene B4, platelet- activating factor, and interleukin (IL)-8, caused a rapid reduction in the IL-1 binding capacity by human polymorphonuclear leukocytes (PMN), a cell type expressing predominantly the IL-1 type II decoy receptor (IL-1 decoy RII). N-t-Boc-Met-Leu-Phe, an antagonist for the FMLP receptor, inhibited the loss of IL-1 binding capacity induced by FMLP. Monocyte chemotactic protein 1, a chemokine related to IL-8 but inactive on PMN, had no effect on IL-1 binding in this cell type. FMLP was selected for further detailed analysis of chemoattractant-induced loss of IL-1 binding by PMN. The action of FMLP was rapid, reaching 50% of its maximum (80%) at 30 s, the earliest measurable time point, and plateauing between 10 and 30 min. Dose-response analysis revealed that maximal reduction of IL-1 binding was reached at FMLP concentrations that were also optimal for chemotaxis (50% effective dose = 5 x 10(-9) M). The loss of IL-1 binding capacity caused by FMLP was determined by a reduction in receptor number with no change in their affinity. The effect of FMLP on IL-1 receptor (IL-1R) was selective in that the PMN surface structures IL-8R...

Interleukin-1β sensitizes abdominal visceral afferents of cats to ischaemia and histamine

Fu, Liang-Wu; Longhurst, John C
Fonte: Blackwell Science Inc Publicador: Blackwell Science Inc
Tipo: Artigo de Revista Científica
Publicado em 15/11/1999 Português
Relevância na Pesquisa
65.68%
Activation of abdominal splanchnic visceral afferents during mesenteric ischaemia induces visceral pain and evokes excitatory cardiovascular responses. Previous studies have shown that interleukin-1β (IL-1β) concentration is increased locally in tissues during ischaemia and reperfusion. Local administration of IL-1β sensitizes somatic afferents to mechanical, thermal and chemical stimulation. Therefore, we hypothesized that IL-1β stimulates or sensitizes splanchnic visceral afferents to ischaemia and to the action of chemical stimuli such as histamine.The concentration of IL-1β in mesenteric lymph and portal venous plasma in anaesthetized cats was measured with an enzyme-linked immunosorbent assay before, during and after 10 min of abdominal ischaemia. The level of IL-1β was significantly increased during ischaemia in lymph, but not in plasma.Discharge activity of single-unit abdominal visceral C fibre afferents was measured from the right thoracic sympathetic chain. Ischaemically sensitive C fibre afferents were identified according to their response to 5–10 min of abdominal ischaemia.Intra-arterial (i.a.) injection of a high dose of IL-1β (500 ng kg−1), but not of a lower dose (i.e. 15, 50 or 150 ng kg−1), stimulated most (six of seven) abdominal visceral afferents.IL-1β (15 ng kg−1...

Bone Morphogenetic Protein (BMP) and Activin Type II Receptors Balance BMP9 Signals Mediated by Activin Receptor-like Kinase-1 in Human Pulmonary Artery Endothelial Cells*

Upton, Paul D.; Davies, Rachel J.; Trembath, Richard C.; Morrell, Nicholas W.
Fonte: American Society for Biochemistry and Molecular Biology Publicador: American Society for Biochemistry and Molecular Biology
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
45.73%
Mutations in transforming growth factor-β (TGF-β) receptor superfamily members underlie conditions characterized by vascular dysplasia. Mutations in endoglin and activin-like kinase receptor 1 (ALK1) cause hereditary hemorrhagic telangiectasia, whereas bone morphogenetic protein type II receptor (BMPR-II) mutations underlie familial pulmonary arterial hypertension. To understand the functional roles of these receptors, we examined their relative contributions to BMP signaling in human pulmonary artery endothelial cells (HPAECs). BMP9 potently and selectively induced Smad1/5 phosphorylation and Id gene expression in HPAECs. Contrary to expectations, BMP9 also stimulated Smad2 activation. Furthermore, BMP9 induced the expression of interleukin 8 and E-selectin. Using small interfering RNA, we demonstrate that the type I receptor, ALK1, is essential for these responses. However, small interfering RNA and inhibitor studies showed no involvement of ALK5 or endoglin. We further demonstrate that, of the candidate type II receptors, BMPR-II predominantly mediated IL-8 and E-selectin induction and mitogenic inhibition by BMP9. Conversely, activin receptor type II (ActR-II) contributed more to BMP9-mediated Smad2 activation. Only abolition of both type II receptors significantly reduced the Smad1/5 and Id responses. Both ALK1 and BMPR-II contributed to growth inhibition of HPAECs...

Follicle-stimulating hormone, interleukin-1, and bone density in adult women

Cannon, Joseph G.; Cortez-Cooper, Miriam; Meaders, Eric; Stallings, Judith; Haddow, Sara; Kraj, Barbara; Sloan, Gloria; Mulloy, Anthony
Fonte: American Physiological Society Publicador: American Physiological Society
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
65.71%
Recent studies have indicated that follicle-stimulating hormone (FSH) promotes bone loss. The present study tested the hypothesis that FSH enhances the activity of bone-resorbing cytokines [interleukin (IL)-1β, tumor necrosis factor (TNF)-α, and IL-6], either by inducing their secretion or by altering their receptor expression. Thirty-six women between the ages of 20 and 50 were assessed for bone mineral density (BMD), reproductive hormone, cytokine ligand and soluble receptor concentrations, and surface expression of cytokine receptors on monocytes. In addition, isolated mononuclear cells were incubated in vitro with exogenous FSH. Univariate regression analyses indicated that BMD was inversely related to serum FSH (r = −0.29 to −0.51, P = 0.03–0.001, depending upon the skeletal site). Physical activity and body composition were also identified as significant factors by multiple regressions. Exogenous FSH induced isolated cells to secrete IL-1β, TNF-α, and IL-6 in proportion to the surface expression of FSH receptors on the monocytes. Endogenous (serum) FSH concentrations correlated with the circulating concentrations of these cytokines. None of these individual cytokines was related to BMD, but the IL-1β to IL-1 receptor antagonist (IL-1Ra) ratio was inversely related to BMD (r = −0.53...

Distinct Contributions of Interleukin-1α (IL-1α) and IL-1β to Innate Immune Recognition of Pseudomonas aeruginosa in the Lung

Al Moussawi, Khatoun; Kazmierczak, Barbara I.
Fonte: American Society for Microbiology Publicador: American Society for Microbiology
Tipo: Artigo de Revista Científica
Publicado em /10/2014 Português
Relevância na Pesquisa
55.67%
The bacterial pathogen Pseudomonas aeruginosa causes acute infections associated with significant morbidity and mortality. P. aeruginosa elicits strong innate immune responses in immunocompetent hosts, and the resulting recruitment of neutrophils to the site of infection is necessary for bacterial clearance. P. aeruginosa lipopolysaccharide and flagellin are recognized by extracellular Toll-like receptors, but the most rapid responses to infection occur when cytosolic receptors sense flagellin or type 3 secretion system (T3SS) structural proteins. The subsequent activation of the NLRC4 inflammasome and caspase-1 generates an interleukin-1β (IL-1β) signal that is required for the rapid neutrophilic response. A T3SS effector, exotoxin U (ExoU), can inhibit activation of the NLRC4 inflammasome and caspase-1. Thus, our observation that IL-1 receptor (IL-1R)-mediated signals were still required to initiate a response to ExoU-producing bacteria was unexpected. As both IL-1α and IL-1β signal via the IL-1R, we examined immune responses in mice lacking either of these cytokines. IL-1β-deficient mice responded to ExoU-producing P. aeruginosa bacteria similarly to wild-type animals; however, IL-1α-deficient mice had an attenuated immune response. The situation was reversed following infections by ExoU-negative bacteria: here...

Développement de modulateurs allostériques peptidiques inhibiteurs de l’activité des récepteurs de l’interleukine 1 et de la vasopressine

Quiniou, Christiane
Fonte: Université de Montréal Publicador: Université de Montréal
Tipo: Thèse ou Mémoire numérique / Electronic Thesis or Dissertation
Português
Relevância na Pesquisa
55.72%
L’approche Module X a été créée dans le but de concevoir de petits peptides modulateurs ayant des propriétés allostériques. Module X reproduit de petites parties des portions extracellulaires flexibles des récepteurs. Ces petits peptides vont interagir en s’interposant entre deux sous unités ou entre deux régions de la même sous-unité qui interagissent par des liens hydrogènes, des ponts salins ou des liens disulfure. Ces régions sont spécialement choisies à l’extérieur du domaine de liaison du ligand orthostérique et sont situées dans les régions inter domaines, la portion juxta membranaire ou dans les boucles. Étant donné que les boucles sont exposées durant les changements de conformation, une séquence peptidique reproduisant certaines régions de ces boucles pourrait s’insérer à un endroit approprié dans la structure où se lier à son partenaire de signalisation dans le complexe protéique, ce qui aurait comme effet de déplacer l’équilibre de l’ensemble vers un état particulier et modulerait ainsi la signalisation. De cette façon, certaines voies de signalisation pourraient être partiellement inhibées tandis que d’autres voies ne seraient pas touchées puisque le ligand orthostérique pourrait toujours se lier au récepteur. Dans une première étude...

Localisation of mRNA for interleukin-1 receptor and interleukin-1 receptor antagonist in the rat ovary

Wang, L.; Brannstrom, M.; Cui, K.H.; Simula, A.; Hart, R.; Maddocks, S.; Norman, R.
Fonte: Society for Endocrinology Publicador: Society for Endocrinology
Tipo: Artigo de Revista Científica
Publicado em //1997 Português
Relevância na Pesquisa
65.63%
Interleukin-1 (IL-1) is a multifunctional cytokine with profound effects on ovarian function. The effects of IL-1 on ovarian steroidogenesis have been demonstrated in several species. IL-1 mRNA levels are increased in the thecal layer of the ovulating follicle and IL-1β has been shown to induce ovulations in vitro. In this study we have investigated the presence and distribution of the mRNAs for type I IL-1 receptor (IL-1RtI) and for the naturally occurring IL-1 receptor antagonist (IL-1ra) in ovaries of adult cycling rats, to elucidate the target cells for IL-1 action. We have demonstrated the presence of mRNA for both substances by in situ hybridisation and reverse transcription PCR. mRNA for IL-1RtI was not found in primordial follicles but was abundant in the granulosa and thecal layer in developing follicles with stronger signals in the granulosa layer. In the preovulatory and ovulatory follicles, there was a further increase in the signal for IL-1RtI mRNA in the thecal layer compared with the granulosa layer. Corpora lutea were weakly positive at all stages and atretic follicles were largely negative. No mRNA was detected in oocytes of any stage. mRNA for IL-1ra showed a similar distribution to that of IL-1RtI. The changes in distribution suggest an action of IL-1 on rat granulosa cells during follicular development and on thecal cells during ovulation.; L-J Wang...

O papel da interleucina-1'beta' produzida no gânglio da raiz dorsal no desenvolvimento da hiperalgesia inflamatória; The role of dorsal root ganglion-produced interleukin-1'beta' in development of inflammatory hyperalgesia

Dionésia Araldi
Fonte: Biblioteca Digital da Unicamp Publicador: Biblioteca Digital da Unicamp
Tipo: Tese de Doutorado Formato: application/pdf
Publicado em 14/05/2012 Português
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85.75%
A liberação de Interleucina-1? (IL-1?) no tecido periférico estimula a síntese de Prostaglandinas (PGs), especialmente, da Prostaglandina-E2 (PGE2), que leva a sensibilização dos nociceptores aferentes primários induzindo a hiperalgesia inflamatória. Recentemente demonstramos que a IL-1? pode ativar diretamente o receptor de Interleucina-1 (IL-1R) do nociceptor aferente periférico e levar a liberação de PGE2 associada ao desenvolvimento da hiperalgesia. A IL-1? também é liberada no Gânglio da Raiz Dorsal (GRD), entretanto a função que a IL-1? desempenha no GRD para o desenvolvimento da hiperalgesia inflamatória ainda não está clara. Portanto, o objetivo deste estudo foi investigar se a liberação de IL-1? e a ativação do Receptor de Interleucina-1 Tipo I (IL-1RI) no GRD estão envolvidos no desenvolvimento da hiperalgesia inflamatória. A administração de IL-1Ra (antagonista natural de receptor IL- 1, 6 ?g) no GRD de ratos preveniu a hiperalgesia mecânica (avaliada por meio do von Frey Eletrônico) induzida pela administração intraplantar (i.pl) de Adjuvante Completo de Freund (CFA, 100 ?L), Carragenina (Cg, 100 ?g) ou IL-1? (0,5 pg), mas não pela administração i.pl de PGE2 (100 ng), avaliadas 3 horas após suas administrações. Além disso...

The inhibitory activity of human interleukin-1 receptor antagonist is enhanced by type II interleukin-1 soluble receptor and hindered by type I interleukin-1 soluble receptor.

Burger, D; Chicheportiche, R; Giri, J G; Dayer, J M
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /07/1995 Português
Relevância na Pesquisa
45.72%
Interleukin-1 (IL-1) is a major proinflammatory cytokine produced by monocytes/macrophages. At the inflammatory site, IL-1 is a potent inducer of the production of prostaglandin E2 (PGE2) and metalloproteinases on fibroblast-like cells, thus triggering tissue damage. The biological activity of IL-1 is counterbalanced by two types of inhibitors: the IL-1 receptor antagonist (IL-1Ra) which competitively binds IL-1 receptor without inducing signal transduction; and IL-1 soluble receptors (IL-1sR) which bind IL-1 and diminish the free concentration of soluble cytokine, thus hampering its binding to the cell surface receptor. Since IL-1sR can also bind IL-1Ra, we studied the simultaneous effects of both inhibitors on the production of interstitial collagenase (C'ase) and PGE2 by human dermal fibroblasts and synovial cells stimulated by either IL-1 alpha or IL-1 beta. IL-1Ra inhibited fibroblast and synovial cell stimulation by approximately 90%, with the exception of C'ase production by synovial cells which was inhibited by approximately 55%. Type I IL-1sR (IL-1sRI) preferentially inhibited IL-1 alpha, whereas type II IL-1sR (IL-1sRII) mainly inhibited IL-1 beta. When IL-1Ra was used simultaneously with IL-1sRI, the final inhibition was lower than that of either of the inhibitors. The simultaneous presence of IL-1Ra and IL-1sRII abolished the IL-1-induced production of PGE2 and C'ase on both dermal fibroblasts and synovial cells...

Wild-type p53-mediated down-modulation of interleukin 15 and interleukin 15 receptors in human rhabdomyosarcoma cells.

De Giovanni, C.; Nanni, P.; Sacchi, A.; Soddu, S.; Manni, I.; D'Orazi, G.; Bulfone-Paus, S.; Pohl, T.; Landuzzi, L.; Nicoletti, G.; Frabetti, F.; Rossi, I.; Lollini, P. L.
Fonte: Nature Publishing Group|1 Publicador: Nature Publishing Group|1
Tipo: Artigo de Revista Científica
Publicado em /12/1998 Português
Relevância na Pesquisa
45.74%
We recently reported that rhabdomyosarcoma cell lines express and secrete interleukin 15 (IL-15), a tightly regulated cytokine with IL-2-like activity. To test whether the p53-impaired function that is frequently found in this tumour type could play a role in the IL-15 production, wild-type p53 gene was transduced in the human rhabdomyosarcoma cell line RD (which harbours a mutated p53 gene), and its effect on proliferation and expression of IL-15 was studied. Arrest of proliferation was induced by wild-type p53; increased proportions of G1-arrested cells and of apoptotic cells were observed. A marked down-modulation of IL-15 expression, at both the mRNA and protein level, was found in p53-transduced cells. Because a direct effect of IL-15 on normal muscle cells has been reported, the presence of IL-15 membrane receptors was studied by cytofluorometric analysis. Rhabdomyosarcoma cells showed IL-15 membrane receptors, which are down-modulated by wild-type p53 transfected gene. In conclusion, wild-type p53 transduction in human rhabdomyosarcoma cells induces the down-modulation of both IL-15 production and IL-15 receptor expression.

Imbalance between interleukin-1 agonists and antagonists: relationship to severity of inflammatory bowel disease

LUDWICZEK, O; VANNIER, E; BORGGRAEFE, I; KASER, A; SIEGMUND, B; DINARELLO, C A; TILG, H
Fonte: Blackwell Science Inc Publicador: Blackwell Science Inc
Tipo: Artigo de Revista Científica
Publicado em /11/2004 Português
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Interleukin (IL)-1 is a key mediator in the pathogenesis of inflammatory bowel disease (IBD). Naturally occurring IL-1 modulators include IL-1 receptor antagonist (IL-1Ra), IL-1 soluble receptor Type I (IL-1sRI), IL-1sRII and IL-1 receptor accessory protein (AcP). Systemic and mucosal levels of IL-1 soluble receptors remain unknown in IBD. Plasma or colonic tissues were obtained from 185 consecutive unselected patients with Crohn's disease (CD) or ulcerative colitis (UC) and from 52 control subjects. Plasma and colonic explant culture supernatants were assessed for IL-1α, IL-1β, IL-1Ra, IL-1sRI and IL-1sRII. Plasma IL-1Ra levels were higher in UC (+93%) than in healthy subjects. IL-1α and IL-1β were not detected. IL-1sRII levels were marginally lower in CD (−10%) and UC (−9%), whereas IL-1sRI levels were elevated in CD (+28%) only. Plasma IL-1sRI levels correlated positively (P < 0·01) with Crohn's disease activity index (r = 0·53), C-reactive protein (r = 0·46) and α1-acid glycoprotein (r = 0·42). In colonic explant cultures, IL-1α and IL-1Ra levels were elevated in non-lesional (+233% and +185% respectively) and lesional CD (+353% and +1069%), lesional UC (+604% and +1138%), but not in non-lesional UC. IL-1β was elevated in lesional UC (+152%) and CD (+128%). In contrast...

Inflammation controls B lymphopoiesis by regulating chemokine CXCL12 expression.

Ueda, Y; Yang, K; Foster, SJ; Kondo, M; Kelsoe, G
Fonte: Universidade Duke Publicador: Universidade Duke
Tipo: Artigo de Revista Científica Formato: 47 - 58
Publicado em 05/01/2004 Português
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Inflammation removes developing and mature lymphocytes from the bone marrow (BM) and induces the appearance of developing B cells in the spleen. BM granulocyte numbers increase after lymphocyte reductions to support a reactive granulocytosis. Here, we demonstrate that inflammation, acting primarily through tumor necrosis factor alpha (TNFalpha), mobilizes BM lymphocytes. Mobilization reflects a reduced CXCL12 message and protein in BM and changes to the BM environment that prevents homing by cells from naive donors. The effects of TNFalpha are potentiated by interleukin 1 beta (IL-1beta), which acts primarily to expand the BM granulocyte compartment. Our observations indicate that inflammation induces lymphocyte mobilization by suppressing CXCL12 retention signals in BM, which, in turn, increases the ability of IL-1beta to expand the BM granulocyte compartment. Consistent with this idea, lymphocyte mobilization and a modest expansion of BM granulocyte numbers follow injections of pertussis toxin. We propose that TNFalpha and IL-1beta transiently specialize the BM to support acute granulocytic responses and consequently promote extramedullary lymphopoiesis.