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PubMed2000

Fc gamma R expression on macrophages is related to severity and chronicity of synovial inflammation and cartilage destruction during experimental immune-complex-mediated arthritis (ICA).

STATEMENT OF FINDINGS: We investigated the role of Fc gamma receptors (Fc gamma Rs) on synovial macrophages in immune-complex-mediated arthritis (ICA). ICA elicited in knee joints of C57BL/6 mice caused a short-lasting, florid inflammation and reversible loss of proteoglycans (PGs), moderate chondrocyte death, and minor erosion of the cartilage. In contrast, when ICA was induced in knee joints of Fc receptor (FcR) gamma-chain(-/-) C57BL/6 mice, which lack functional Fc gamma RI and RIII, inflammation and cartilage destruction were prevented. When ICA was elicited in DBA/1 mice, a very severe, chronic inflammation was observed, and significantly more chondrocyte death and cartilage erosion than in arthritic C57BL/6 mice. The synovial lining and peritoneal macrophages of naïve DBA/1 mice expressed a significantly higher level of Fc gamma Rs than was seen in C57BL/6 mice. Moreover, elevated and prolonged expression of IL-1 was found after stimulation of these cells with immune complexes. Zymosan or streptococcal cell walls caused comparable inflammation and only mild cartilage destruction in all strains. We conclude that Fc gamma R expression on synovial macrophages may be related to the severity of synovial inflammation and cartilage destruction during ICA.

Animals↗
PubMed2006

Role of the mediator complex in nuclear hormone receptor signaling.

Mediator is an evolutionarily conserved multisubunit protein complex that plays a key role in regulating transcription by RNA polymerase II. The complex functions by serving as a molecular bridge between DNA-bound transcriptional activators and the basal transcription apparatus. In humans, Mediator was first characterized as a thyroid hormone receptor (TR)-associated protein (TRAP) complex that facilitates ligand-dependent transcriptional activation by TR. More recently, Mediator has been established as an essential coactivator for a broad range of nuclear hormone receptors (NRs) as well as several other types of gene-specific transcriptional activators. A single subunit of the complex, MED1/TRAP220, is required for direct ligand-dependent interactions with NRs. Mediator coactivates NR-regulated gene expression by facilitating the recruitment and activation of the RNA polymerase II-associated basal transcription apparatus. Importantly, Mediator acts in concert with other NR coactivators involved in chromatin remodeling to initiate transcription of NR target genes in a multistep manner. In this review, we summarize the functional role of Mediator in NR signaling pathways with an emphasis on the underlying molecular mechanisms by which the complex interacts with NRs and subsequently facilitates their action. We also focus on recent advances in our understanding of TRAP/Mediator's pathophysiological role in mammalian disease and development.

Animals↗
PubMed1989

Mechanism of immune complex-mediated damage: induction of interleukin 1 by immune complexes and synergy with interferon-gamma and tumor necrosis factor-alpha.

The ability of immune complexes derived from patients with type II mixed essential cryoglobulinemia to trigger the production of interleukin 1 (IL 1) was investigated. Immune complexes containing either IgM/IgG or IgA/IgG aggregates were shown to induce IL 1 production in human peripheral blood monocyte-enriched populations. Interferon-gamma alone did not induce detectable IL 1, but increased the IL 1 production induced by the immune complexes. Tumor necrosis factor-alpha, which is a potent inducer of IL 1, also enhanced IL 1 production following stimulation with suboptimal doses of the immune complex. The findings suggest that immune complexes may induce inflammation partly due to their capacity to induce the synthesis of IL 1.

Antigen-Antibody Complex↗
PubMed2001

Inhibition of immune-complex mediated dermal inflammation in rats following either oral or topical administration of a small molecule C5a receptor antagonist.

1. Initiation of a peritoneal Arthus reaction by deposition of immune-complexes results in vascular leakage, polymorphonuclear leukocyte (PMN) infiltration, and tumour necrosis factor alpha (TNFalpha) and interleukin-6 (IL-6) production. We now demonstrate in rats that oral administration of the C5a receptor antagonist AcPhe[Orn-Pro-D-Cyclohexylalanine-Trp-Arg] (AcF-[OPdChaWR]; 1 - 10 mg kg(-1) 30 min prior to immune-complex deposition) inhibits these inflammatory markers in the peritoneal Arthus reaction. 2. Initiation of a dermal Arthus reaction resulted in a significant increase in vascular leakage, PMN infiltration, systemic production of TNFalpha and pathological changes in the dermis. 3. Pretreatment of rats with AcF-[OPdChaWR] either intravenously (1 mg kg(-1) 10 min prior to immune-complex deposition) or orally (1 - 10 mg kg(-1) 30 min prior to immune-complex deposition) significantly inhibited immune-complex mediated dermal vascular leakage and systemic cytokine production. Topical pretreatment with AcF-[OPdChaWR] (400 microg site(-1) in 10% dimethyl sulphoxide 10 min prior to immune-complex deposition) also inhibited vascular leakage, as well as histopathological changes associated with a dermal Arthus reaction. 4. Oral administration of 3 mg kg(-1) AcF-[OPdChaWR] resulted in the appearance of the drug in plasma within 5 min, with peak blood levels approximately 0.3 microM reached within 20 min. The plasma elimination half-life was approximately 70 min. The oral activity and bioavailability of AcF-[OPdChaWR], its activity when applied topically to the skin, suggest that small molecule C5a receptor antagonists may have therapeutic utility in dermal inflammatory disorders involving complement activation. 5. This is the first demonstration for either an orally or topically active C5a receptor antagonist, and suggests that small molecule C5a antagonists may have therapeutic utility when given by multiple routes of application.

Administration, Oral↗
PubMed2003

Coordinate expression of activating Fc gamma receptors I and III and inhibiting Fc gamma receptor type II in the determination of joint inflammation and cartilage destruction during immune complex-mediated arthritis.

OBJECTIVE: To study the role of the activating Fc gamma receptor types I and III (Fc gamma RI and Fc gamma RIII, respectively) and the inhibiting Fc gamma receptor II (Fc gamma RII) in inflammation and in various aspects of cartilage destruction during arthritis that is solely induced by immune complexes. METHODS: Immune complex-mediated arthritis (ICA) was passively induced by lysozyme-antilysozyme complexes in Fc gamma RI-, Fc gamma RIII-, and Fc gamma RII-knockout mice and their wild-type controls. Total knee joints were isolated to study inflammation and cartilage destruction (loss of proteoglycans [PGs], chondrocyte death, matrix metalloproteinase [MMP]-mediated neoepitope [VDIPEN] expression, and erosion). The presence of an active phenotype of macrophages was studied by detection of myeloid-related proteins 8 and 14 (MRP8 and MRP14, respectively). RESULTS: Influx and activation of inflammatory cells (MRP expression) during ICA was decreased in Fc gamma RIII-deficient mice and enhanced in mice lacking Fc gamma RII. Mild cartilage destruction reflected by loss of PGs was consistent with the degree of inflammation. Mice lacking Fc gamma RIII showed almost no PG depletion, whereas in Fc gamma RII(-/-) mice, PG depletion was increased 3-7-fold in various cartilage areas. Initiation of erosive cartilage destruction, as reflected by MMP-mediated VDIPEN expression, was reduced in Fc gamma RIII(-/-) and Fc gamma RI(-/-) mice, directing the two different critical steps of cellular influx and subsequent activation. These aspects were enhanced in Fc gamma RII(-/-) mice. In Fc gamma RI(-/-) and Fc gamma RIII(-/-) mice, VDIPEN expression was 90-99% lower, whereas in Fc gamma RII(-/-) mice, VDIPEN expression was increased 4-fold. Chondrocyte death was reduced in Fc gamma RIII(-/-) mice (68% lower) and enhanced in Fc gamma RII(-/-) mice (6-12-fold higher). Progression of arthritis and erosion of the cartilage surface were markedly elevated in Fc gamma RII(-/-) arthritic joints. CONCLUSION: During ICA, Fc gamma RIII is the dominant activating receptor mediating joint inflammation, whereas both Fc gamma RI and Fc gamma RIII are involved in cartilage destruction. Fc gamma RII inhibits both joint inflammation and severe cartilage destruction during ICA.

Animals↗
PubMed2004

Correction of translational defects in patient-derived mutant mitochondria by complex-mediated import of a cytoplasmic tRNA.

A variety of clinical disorders result from mutations in mitochondrial tRNA genes, leading to translational defects. We show here that a protein complex from the kinetoplastid protozoon Leishmania induces specific, ATP-dependent import of human cytoplasmic tRNA(1)(Lys) into human mitochondria in vitro. The imported tRNA undergoes efficient aminoacylation within the organelle and supports organellar protein synthesis. Moreover, translation in mitochondria from patients with myclonic epilepsy with ragged red fibers (MERRF) and Kearns-Sayre syndrome (KSS), containing mutant tRNA(Lys) genes, is stimulated to near-wild-type levels and the formation of aberrant polypeptides suppressed by complex-mediated import. These results suggest a novel way to introduce RNAs for the modulation of mitochondrial gene expression.

Adenosine Triphosphate↗
PubMed1991

Clozapine attenuates N-methyl-D-aspartate receptor complex-mediated responses in vivo: tentative evidence for a functional modulation by a noradrenergic mechanism.

Recent studies revealed a role for dopamine and noradrenaline in the etiology of ischemia-induced neuronal cell death. In the present investigation, the modulation by clozapine, an atypical antipsychotic agent that interacts with adrenergic receptors, of N-methyl-D-aspartate (NMDA) receptor complex-mediated events were studied by examining its effects on levels of cGMP in the cerebellum. Clozapine decreased basal levels of cGMP in the cerebellum and antagonized harmaline-, methamphetamine-, pentylenetetrazol- and D-serine-induced increases in levels of cGMP with ED50 values of 3.9, 2.36, 2.13 and 2.1 mg/kg (i.p.). However, clozapine (1.25-25 mg/kg) did not attenuate the quisqualate-induced increases in levels of cGMP, indicating a specific modulation of events modulated by the NMDA receptor complex. Antagonists of dopamine (D2), serotonin (5-HT)-5-HT1, 5-HT2 and 5-HT3 [haloperidol, propranolol, ritanserin, ICS 205-930 [(3-tropanyl-indole-3-carboxylate methiodide)] respectively], did not reverse the response to harmaline. However, WB-4101 [(2,6-dimethoxy-phenoxyethyl)aminomethyl-1,4-benzodioxane HCl], and alpha 1-adrenergic antagonist, reversed harmaline-, D-serine-, PTZ- and MA-induced increases in levels of cGMP, indicating an adrenergic modulation of the events mediated by the NMDA receptor complex. Intracerebellar and intracerebroventricular administration of clozapine and intracerebellar administration of WB-4101 reversed the D-serine-induced response, indicating a central locus of action. These results indicated that clozapine modulates levels of cGMP predominantly through its interactions with central adrenergic receptors.

Adrenergic alpha-Antagonists↗
PubMed2000

TFIIH is negatively regulated by cdk8-containing mediator complexes.

The mammalian cyclin-dependent kinase 8 (cdk8) gene has been linked with a subset of acute lymphoblastic leukaemias, and its corresponding protein has been functionally implicated in regulation of transcription. Mammalian cdk8 and cyclin C, and their respective yeast homologues, Srb10 and Srb11, are components of the RNA polymerase II holoenzyme complex where they function as a protein kinase that phosphorylates the carboxy-terminal domain (CTD) of the largest subunit of RNA polymerase II (ref. 7). The yeast SRB10 and SRB11 genes have been implicated in the negative regulation of transcription. The cdk8/cyclin C protein complex is also found in a number of mammalian Mediator-like protein complexes, which repress activated transcription independently of the CTD in vitro. Here we show that cdk8/cyclin C can regulate transcription by targeting the cdk7/cyclin H subunits of the general transcription initiation factor IIH (TFIIH). cdk8 phosphorylates mammalian cyclin H in the vicinity of its functionally unique amino-terminal and carboxy-terminal alpha-helical domains. This phosphorylation represses both the ability of TFIIH to activate transcription and its CTD kinase activity. In addition, mimicking cdk8 phosphorylation of cyclin H in vivo has a dominant-negative effect on cell growth. Our results link the Mediator complex and the basal transcription machinery by a regulatory pathway involving two cyclin-dependent kinases. This pathway appears to be unique to higher organisms.

Amino Acids↗
PubMed1993

Cyclic amphipathic peptide-DNA complexes mediate high-efficiency transfection of adherent mammalian cells.

A DNA transfection protocol has been developed that makes use of the cyclic cationic amphipathic peptide gramicidin S and dioleoyl phosphatidylethanolamine. The DNA complex is formed by mixing gramicidin S with DNA at a 1:1 charge ratio and then adding phosphatidylethanolamine at a lipid/peptide molar ratio of 5:1. The complex mediates rapid association of DNA with cells and leads to transient expression levels of beta-galactosidase ranging from 1 to 30% of the transfected cells, with long-term expression being about an order of magnitude lower. The respective roles of peptide and phospholipid are not yet resolved but optimal transfection requires both the cyclic peptide and the hexagonal phase-competent phospholipid PtdEtn. Transfection in CV-1 cells is not affected by lysomotrophic agents, which suggests that DNA entry into the cell is via the plasma membrane. This technique that is simple, economical, and reproducible mediates transfection levels up to 20-fold higher than cationic liposomes in adherent mammalian cells.

Animals↗
PubMed2007

Idiopathic hypocomplementemic immune-complex-mediated tubulointerstitial nephritis.

BACKGROUND: A 42-year-old man presenting with flank pain was found to have renal failure with severe hypocomplementemia and eosinophilia. INVESTIGATIONS: Physical examination, laboratory testing, renal ultrasonography, and renal biopsies. DIAGNOSIS: Acute immune-complex-mediated tubulointerstitial nephritis. MANAGEMENT: Immunosuppressive therapy with 1 mg/kg/day prednisone.

Adult↗
PubMed2005

Neutrophil-derived serine proteases in immune complex-mediated diseases.

Neutrophil-derived serine proteases play an important role in fighting infections. However, emerging data suggest that these proteases also regulate noninfectious inflammatory responses. Loss-of-function mutations in serine proteases have provided critical insights into the significance of these serine proteases in initiating and amplifying immune complex-mediated diseases.

Animals↗
PubMed1987

Amelioration of immune complex-mediated glomerulonephritis by synthetic protease inhibitors.

Proteases are involved in the pathogenesis of inflammatory diseases by participating in the activation of mediator systems and by producing proteolytic tissue injury. Homeostatic control of inflammation is accomplished in part by physiologic protease inhibitors. The authors investigated the effectiveness of a number of synthetic protease inhibitors in ameliorating the glomerular injury induced by immune complex-mediated glomerulonephritis in mice. Two amidine-type protease inhibitors, bis (5-amidino-2-benzimidazolyl)methane and 1,2-bis (5-amidino-2-benzimidazolyl)ethane, had the greatest effects. They caused a marked reduction in glomerular necrosis (P less than 0.001) but did not affect the amount or site of immune complex localization or leukocyte influx. The inhibition constants of the protease inhibitors against nine purified physiologic proteases were determined. These results were discussed in relation to the effectiveness of the protease inhibitors in reducing glomerular injury. This investigation indicates that the administration of synthetic protease inhibitors can have a beneficial effect on immune-mediated inflammatory injury.

Amidines↗
PubMed2002

Caenorhabditis elegans unc-37/groucho interacts genetically with components of the transcriptional mediator complex.

Groucho functions as a general corepressor by modulating chromatin structure and has a widespread role in many developmental processes. Here we show that Groucho may also interact with the basal transcriptional machinery. Mutations in Caenorhabditis elegans groucho interact with mutations in components of the transcriptional Mediator complex, resulting in synthetic lethality and loss of male sensory neurons.

Animals↗
PubMed2002

Formation of the approximately 350-kDa Apg12-Apg5.Apg16 multimeric complex, mediated by Apg16 oligomerization, is essential for autophagy in yeast.

Autophagy, responsible for the delivery of cytoplasmic components to the lysosome/vacuole for degradation, is the major degradative pathway in eukaryotic cells. This process requires a ubiquitin-like protein conjugation system, in which Apg12 is covalently bound to Apg5. In the yeast Saccharomyces cerevisiae, the Apg12-Apg5 conjugate further interacts with a small coiled-coil protein, Apg16. The Apg12-Apg5 and Apg16 are localized in the cytosol and pre-autophagosomal structures and play an essential role in autophagosome formation. Here we show that the Apg12-Apg5 conjugate and Apg16 form a approximately 350-kDa complex in the cytosol. Because Apg16 was suggested to form a homo-oligomer, we generated an in vivo system that allowed us to control the oligomerization state of Apg16. With this system, we demonstrated that formation of the approximately 350-kDa complex and autophagic activity depended on the oligomerization state of Apg16. These results suggest that the Apg12-Apg5 conjugate and Apg16 form a multimeric complex mediated by the Apg16 homo-oligomer, and formation of the approximately 350-kDa complex is required for autophagy in yeast.

Autophagy↗
PubMed1978

Behçet's disease associated with a lymphoproliferative disorder, mixed cryoglobulinemia, and an immune complex mediated vasculitis.

A woman, now 59 has been followed for 13 years with several manifestations of Behçet's disease. These were aphthous stomatitis, genital ulcers, uveitis causing blindness, recurrent erythema nodosum, and synovitis. In 1970 a poorly differentiated diffuse lymphocytic lymphoma appeared and was treated with radiotherapy. In 1976 she developed a mixed cryoglobulinemia and an immune complex mediated vasculitis manifested by purpura and neuropathy which improved on prednisone and chlorambucil therapy. The subsequent course of her lymphoproliferative disorder suggest that it was in fact benign.

Antigen-Antibody Complex↗
PubMed1980

A model of immune complex-mediated pleuropulmonary injury; evidence of deposition of circulating immune complexes in the lung.

Severe acute, diffuse lung inflammation was induced in rabbits immunized to bovine serum albumin (BSA) and subsequently challenged with BSA intrapleurally. Evidence suggesting involvement of circulating immune complexes in the pathogenesis of lung injury in these rabbits include 1) positive lung immunofluorescence, 2) a fall in serum hemolytic complement, 3) diffuse bilateral involvement despite unilateral antigen challenge, and 4) absence of these findings in control rabbits. Further investigation with this model may provide insight into the processes involved in the deposition of immune complexes in the lung and the mechanisms of lung injury provoked by immune complex deposition.

Animals↗
PubMed2002

Involvement of dipeptidyl peptidase IV in immune complex-mediated glomerulonephritis.

Dipeptidyl peptidase IV (DPPIV) is widely expressed in many tissues; however, its precise biological function is poorly understood. One of its possible physiologic roles is an involvement in the immune system, which plays a pivotal role in the pathogenesis of glomerulonephritis. The present study focused on the involvement of DPPIV in immune complex-mediated glomerulonephritis. Experimental nephritis was induced by anti-Thy-1.1 monoclonal antibody E30 using Wistar or F344 rats. The application of a new monoclonal antibody against DPPIV, F16, completely suppressed E30-induced proteinuria and mesangial proliferation in Wistar rats, whereas these preventive effects of F16 were not observed in F344 rats, which spontaneously lack DPPIV protein. Treatment with F16 inhibited glomerular deposition of complement C3 and complement C4 after the binding of E30 to the mesangial cell surface. Because the preventive effect of F16 was attributable to suppression of the complement cascade, we examined its influences on complement-dependent mesangial cell lysis in vitro. We discovered that the complement cascade was markedly inactivated in F16-treated Wistar rat serum but not in F16-treated F344 rats. These results indicate that DPPIV may play a somewhat crucial role in regulating the complement cascade and that inhibition of DPPIV may serve as a new target for preventing complement-dependent tissue injury.

Animals↗
PubMed1989

Captopril-induced hypersensitivity lung disease. An immune-complex-mediated phenomenon.

Captopril has not yet been included in the list of drugs causing hypersensitivity lung disease. We report a patient with hypertension, congestive heart failure, and chronic renal failure who, when rechallenged with captopril, developed upper lung field infiltrates associated with productive cough and striking peripheral eosinophilia. Gallium scan, transbronchial biopsy histologic findings, and direct immunofluorescent study were consistent with an immune-complex-mediated hypersensitivity reaction. There was no other etiology discovered for the patient's eosinophilia, nor was there evidence for an infectious etiology to explain his presentation.

Aged↗