serpin function
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Serpins are widely distributed and functionally diverse inhibitors of serine proteases. Ticks secrete serpins with anti-coagulation, anti-inflammatory, and immunomodulatory activities via their saliva into the feeding cavity to modulate host's hemostatic and immune reaction initiated by the insertion of tick's mouthparts into skin. The suppression of the host's immune response not only allows ticks to feed on a host for several days but also creates favorable conditions for the transmission of tick-borne pathogens. Herein we present the functional and structural characterization of Iripin-1 (Ixodes ricinus serpin-1), whose expression was detected in the salivary glands of the tick Ixodes ricinus, a European vector of tick-borne encephalitis and Lyme disease. Of 16 selected serine proteases, Iripin-1 inhibited primarily trypsin and further exhibited weaker inhibitory activity against kallikrein, matriptase, and plasmin. In the mouse model of acute peritonitis, Iripin-1 enhanced the production of the anti-inflammatory cytokine IL-10 and chemokines involved in neutrophil and monocyte recruitment, including MCP-1/CCL2, a potent histamine-releasing factor. Despite increased chemokine levels, the migration of neutrophils and monocytes to inflamed peritoneal cavities was significantly attenuated following Iripin-1 administration. Based on the results of in vitro experiments, immune cell recruitment might be inhibited due to Iripin-1-mediated reduction of the expression of chemokine receptors in neutrophils and adhesion molecules in endothelial cells. Decreased activity of serine proteases in the presence of Iripin-1 could further impede cell migration to the site of inflammation. Finally, we determined the tertiary structure of native Iripin-1 at 2.10 Å resolution by employing the X-ray crystallography technique. In conclusion, our data indicate that Iripin-1 facilitates I. ricinus feeding by attenuating the host's inflammatory response at the tick attachment site.
- MeSH
- antiflogistika farmakologie MeSH
- chemokiny MeSH
- endoteliální buňky metabolismus MeSH
- klíště * metabolismus MeSH
- monocyty metabolismus MeSH
- myši MeSH
- serpiny * metabolismus MeSH
- trypsin MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Intramural MeSH
Th17 cells constitute a subset of CD4(+) T lymphocytes that play a crucial role in protection against extracellular bacteria and fungi. They are also associated with tissue injury in autoimmune and inflammatory diseases. Here, we report that serpin from the tick Ixodes ricinus, IRS-2, inhibits Th17 differentiation by impairment of the interleukin-6 (IL-6)/STAT-3 signaling pathway. Following activation, mature dendritic cells produce an array of cytokines, including the pleiotropic cytokine IL-6, which triggers the IL-6 signaling pathway. The major transcription factor activated by IL-6 is STAT-3. We show that IRS-2 selectively inhibits production of IL-6 in dendritic cells stimulated with Borrelia spirochetes, which leads to attenuated STAT-3 phosphorylation and finally to impaired Th17 differentiation. The results presented extend the knowledge about the effect of tick salivary serpins on innate immunity cells and their function in driving adaptive immune responses.
- MeSH
- Borrelia imunologie MeSH
- buněčná diferenciace účinky léků MeSH
- buňky Th17 účinky léků fyziologie MeSH
- dendritické buňky účinky léků fyziologie MeSH
- interleukin-6 antagonisté a inhibitory metabolismus MeSH
- klíště MeSH
- myši inbrední C57BL MeSH
- serpiny metabolismus MeSH
- signální transdukce účinky léků MeSH
- transkripční faktor STAT3 antagonisté a inhibitory metabolismus MeSH
- zvířata MeSH
- Check Tag
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Tick saliva is a rich source of antihemostatic, anti-inflammatory, and immunomodulatory molecules that actively help the tick to finish its blood meal. Moreover, these molecules facilitate the transmission of tick-borne pathogens. Here we present the functional and structural characterization of Iripin-8, a salivary serpin from the tick Ixodes ricinus, a European vector of tick-borne encephalitis and Lyme disease. Iripin-8 displayed blood-meal-induced mRNA expression that peaked in nymphs and the salivary glands of adult females. Iripin-8 inhibited multiple proteases involved in blood coagulation and blocked the intrinsic and common pathways of the coagulation cascade in vitro. Moreover, Iripin-8 inhibited erythrocyte lysis by complement, and Iripin-8 knockdown by RNA interference in tick nymphs delayed the feeding time. Finally, we resolved the crystal structure of Iripin-8 at 1.89 Å resolution to reveal an unusually long and rigid reactive center loop that is conserved in several tick species. The P1 Arg residue is held in place distant from the serpin body by a conserved poly-Pro element on the P' side. Several PEG molecules bind to Iripin-8, including one in a deep cavity, perhaps indicating the presence of a small-molecule binding site. This is the first crystal structure of a tick serpin in the native state, and Iripin-8 is a tick serpin with a conserved reactive center loop that possesses antihemostatic activity that may mediate interference with host innate immunity.
- MeSH
- aktivace komplementu účinky léků imunologie fyziologie MeSH
- erytrocyty metabolismus MeSH
- exprese genu genetika MeSH
- hemokoagulace účinky léků fyziologie MeSH
- klíště enzymologie genetika metabolismus MeSH
- komplement metabolismus MeSH
- lymeská nemoc MeSH
- nymfa MeSH
- proteiny členovců metabolismus MeSH
- regulace genové exprese genetika MeSH
- serpiny metabolismus ultrastruktura MeSH
- slinné žlázy metabolismus MeSH
- sliny chemie MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- MeSH
- antithrombin III MeSH
- biologická evoluce MeSH
- DNA MeSH
- lidé MeSH
- ovalbumin MeSH
- sekvenční analýza MeSH
- serpiny fyziologie chemie MeSH
- Check Tag
- lidé MeSH
Tick saliva has been extensively studied in the context of tick-host interactions because it is involved in host homeostasis modulation and microbial pathogen transmission to the host. Accumulated knowledge about the tick saliva composition at the molecular level has revealed that serine protease inhibitors play a key role in the tick-host interaction. Serpins are one highly expressed group of protease inhibitors in tick salivary glands, their expression can be induced during tick blood-feeding, and they have many biological functions at the tick-host interface. Indeed, tick serpins have an important role in inhibiting host hemostatic processes and in the modulation of the innate and adaptive immune responses of their vertebrate hosts. Tick serpins have also been studied as potential candidates for therapeutic use and vaccine development. In this review, we critically summarize the current state of knowledge about the biological role of tick serpins in shaping tick-host interactions with emphasis on the mechanisms by which they modulate host immunity. Their potential use in drug and vaccine development is also discussed.
- MeSH
- inhibitory serinových proteinas fyziologie MeSH
- klíšťata * metabolismus MeSH
- serpiny * metabolismus MeSH
- slinné žlázy metabolismus MeSH
- sliny metabolismus MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Metabolický syndrom, který výrazně zvyšuje kardiovaskulární morbiditu, mortalitu ariziko rozvoje diabetes mellitus 2. typu, vsoučasné době dosahuje epidemických proporcí. Tato komplexní porucha vyžaduje urgentní vývoj nových farmakoterapeutických řešení. Patofyziologické mechanismy vedoucí k rozvoji tohoto syndromu nejsou dosud plně objasněny, nicméně se zdá zřejmé, že k jeho rozvoji přispívá řada metabolických dysregulací. Za potenciálně slibný cíl pro vývoj nových léčiv se považuje dysregulace endokrinních aparakrinních funkcí tukové tkáně. Specifické adipokiny, což jsou proteiny secernované tukovou tkání s jistými pleiotropními účinky, jsou silně asociovány s regulací energetického metabolismu, chuti k jídlu, inzulinové signální dráhy, senzitivity periferních tkání k inzulinu aprozánětlivému stavu spojenému smetabolickým syndromem. Cílem této práce je poskytnout stručný přehled endokrinních aparakrinních funkcí tukové tkáně ve spojitosti s rozvojem metabolického syndromu, jeho patofyziologických podkladů apoukázat na některé adipokiny jako potenciální cíle pro vývoj nových farmakoterapeutických přístupů.
Metabolic syndrome, acondition increasing cardiovascular morbidity, mortality and risk for diabetes mellitus type 2, is currently worldwide reaching epidemic proportions. This complex disorder represents an urgent challenge for new pharmacotherapeutic strategies formulation. Pathophysiological mechanisms underlying metabolic syndrome are not completely understood, nevertheless growing evidence is supporting the hypothesis that multiple metabolic dysregulations do contribute to its development. Apotential target for pharmacological intervention is considered to be dysregulation of adipose tissue endocrine/paracrine function. Specific adipokines, proteins secreted by the adipose tissue, with some pleiotropic effects, have been identified with strong association to regulation of energy metabolism, appetite, insulin signaling, tissue insulin sensitivity and the proinflammatory state related to metabolic syndrome. The aim of this paper is to provide abrief overview of endocrine/paracrine functions of the adipose tissue with regard to metabolic syndrome development and pathophysiology and particular adipokines as potential targets for innovative pharmacotherapeutic approaches.
- Klíčová slova
- omentin, vaspin,
- MeSH
- adipokiny * metabolismus MeSH
- adiponektin metabolismus MeSH
- cytokiny metabolismus MeSH
- GPI-vázané proteiny metabolismus MeSH
- inzulinová rezistence MeSH
- lektiny metabolismus MeSH
- leptin metabolismus MeSH
- lidé MeSH
- metabolický syndrom * etiologie metabolismus patofyziologie MeSH
- nikotinamidfosforibosyltransferasa metabolismus MeSH
- proteiny vázající mastné kyseliny metabolismus MeSH
- resistin metabolismus MeSH
- serpiny metabolismus MeSH
- tuková tkáň * metabolismus patofyziologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
- přehledy MeSH
Antitrombin je jeden z nejdůležitějších inhibitorů serinových proteáz (serpinů), především trombinu a faktoru Xa. Jeho vrozený nedostatek je řazen mezi trombofílie. Klinicky se projevuje hlavně žilními trombózami včetně embolie plic a atypickou lokalizací trombóz, jsou popsány i arteriální trombózy, komplikace v graviditě. Laboratorně stanovujeme jeho inhibiční aktivitu, v případě vrozeného defektu i antigen. Problematické se ukazuje stanovení inhibiční aktivity u osob s defektem typu II, kdy běžně používané testy (většinou anti-Xa, někdy i anti-IIa ) nemusí defekt zachytit a je nezbytné doplnit genetické vyšetření.
Antithrombin is one the most important serine protease inhibitors (termed the serpin family), especially of thrombin and factor Xa. Its inherited deficiency is associated with an increased risk of venous thrombosis, pulmonary embolism and thrombosis in atypical localizations. There are even a few reports about arterial thrombosis associated with this deficiency. Pregnancy complications can occur in women with antithrombin deficiency. We use functional assays are used to determine antithrombin (inhibitory) activity in the laboratory. The antigenic assay is used only to define the type of deficiency in the case of impaired antithrombin activity. FXa inhibition-based antithrombin assays appear to be the most widely used routine method. It is important to realize that it is possible that not all type II deficiencies can be detected using this assay as various defects have different findings and the results can in some cases be within normal range. In such cases, the diagnosis can be made only by genetic analysis.
- MeSH
- antithrombinové proteiny genetika nedostatek MeSH
- antitrombiny * fyziologie metabolismus MeSH
- biochemická analýza krve * MeSH
- dospělí MeSH
- faktor Xa metabolismus MeSH
- hemokoagulace * MeSH
- hemostáza MeSH
- lidé MeSH
- mladiství MeSH
- mutace MeSH
- riziko MeSH
- rizikové faktory MeSH
- serpiny * fyziologie klasifikace metabolismus MeSH
- těhotenství MeSH
- tromboembolie * genetika MeSH
- trombóza * genetika MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- těhotenství MeSH
- ženské pohlaví MeSH
The clinical course of chronic renal diseases and their progression to ESRD is highly variable. The strongest predictors of poor outcome of IgAN involve hypertension, severe proteinuria and elevated serum creatinine level. Different candidate gene polymorphisms have been advocated as possible modulators of the progression of IgAN. Megsin belongs to the serpin superfamily and was mapped to chromosome 18q21.3. Megsin plays a role in the regulation of a wide variety of processes in mesangial cells, such as matrix metabolism, cell proliferation, and apoptosis. Overexpression of Megsin might lead to mesangial dysfunction, and impair degradation of the mesangial matrix and disposal of immune complexes. The expression of Megsin is upregulated in a variety of glomerular diseases with mesangial injury in humans and in animal models. We investigated a possible association of two C2093T, C2180T polymorphisms of the megsin gene with the progression of IgAN towards ESRD, as well as the haplotype reconstruction of megsin gene polymorphisms and clinical manifestation of IgAN. We examined a group of 197 pts with histologically proven IGAN (84 pts with normal renal function, 113 pts with progressive renal insufficiency); as a control group we used 61 genetically unrelated healthy subjects. DNA samples from collected blood were genotyped for two singlenucleotide polymorphisms of megsin C2093T, C2180T by means of PCR with defined primers, electrophoresis on 2% agarose gel, UV light visualization and direct sequencing. The megsin genotype distribution showed no differences among the groups of IgAN with normal renal function, progressive renal insufficiency and the control group. According to haplotype analysis, the TT haplotype (defined as T-2093, T-2180 alleles) was substantially more frequent in pts with IgAN and normal renal function (Table 1, P = 0.025; Table 3, P = 0.062). Pts in the progressive group showed significantly higher levels of 24-h UP (3.53 +/- 2.80 vs 2.06 +/- 2.06, P = 0.042; Table 10), diastolic blood pressure (92.89 +/- 15.66 vs 84.93 +/- 10.43, P = 0.047; Table 10) and almost significantly systolic blood pressure (150.79 +/- 32.88 vs 135.21 +/- 14.88, P = 0.058; Table 10). We confirmed the negative prognostic influence of hypertension and proteinuria on the progression of IgAN in Czech pts. We found out that the TT haplotype (defined as T-2093, T-2180 alleles) could play a protective role in the progression of IgAN. In our Czech population, we excluded the negative influence of the 2093C-2180T haplotype, which was proposed by Chinese studies.
Netherton syndrome (NS) is a severe skin disease caused by the loss of protease inhibitor LEKTI, which leads to the dysregulation of epidermal proteases and severe skin-barrier defects. KLK5 was proposed as a major protease in NS pathology, however its inactivation is not sufficient to rescue the lethal phenotype of LEKTI-deficient mice. In this study, we further elucidated the in vivo roles of the epidermal proteases in NS using a set of mouse models individually or simultaneously deficient for KLK5 and KLK7 on the genetic background of a novel NS-mouse model. We show that although the ablation of KLK5 or KLK7 is not sufficient to rescue the lethal effect of LEKTI-deficiency simultaneous deficiency of both KLKs completely rescues the epidermal barrier and the postnatal lethality allowing mice to reach adulthood with fully functional skin and normal hair growth. We report that not only KLK5 but also KLK7 plays an important role in the inflammation and defective differentiation in NS and KLK7 activity is not solely dependent on activation by KLK5. Altogether, these findings show that unregulated activities of KLK5 and KLK7 are responsible for NS development and both proteases should become targets for NS therapy.
