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61.
Acute phase mediators modulate thrombin-activable fibrinolysis inhibitor (TAFI) gene expression in HepG2 cells 总被引:8,自引:0,他引:8
Boffa MB Hamill JD Maret D Brown D Scott ML Nesheim ME Koschinsky ML 《The Journal of biological chemistry》2003,278(11):9250-9257
Thrombin-activable fibrinolysis inhibitor (TAFI) has recently been identified as a positive acute phase protein in mice, an observation that may have important implications for the interaction of the coagulation, fibrinolytic, and inflammatory systems. Activated TAFI (TAFIa) inhibits fibrinolysis by removing the carboxyl-terminal lysines from partially degraded fibrin that are important for maximally efficient plasminogen activation. In addition, TAFIa has been shown to be capable of removing the carboxyl-terminal arginine residues from the anaphylatoxins and bradykinin, thus implying a role for the TAFI pathway in the vascular responses to inflammation. In the current study, we investigated the ability of acute phase mediators to modulate human TAFI gene expression in cultured human hepatoma (HepG2) cells. Surprisingly, we found that treatment of HepG2 cells with a combination of interleukin (IL)-1 and IL-6 suppressed endogenous TAFI mRNA abundance in HepG2 cells (~60% decrease), while treatment with IL-1 or IL-6 alone had no effect. Treatment with IL-1 and/or IL-6 had no effect on TAFI promoter activity as measured using a luciferase reporter plasmid containing the human TAFI 5'-flanking region, whereas treatment with IL-1 and IL-6 in combination, but not alone, decreased the stability of the endogenous TAFI mRNA. Treatment with the synthetic glucocorticoid dexamethasone resulted in a 2-fold increase of both TAFI mRNA levels and promoter activity. We identified a functional glucocorticoid response element (GRE) in the human TAFI promoter between nucleotides 92 and 78. The GRE was capable of binding the glucocorticoid receptor, as assessed by gel mobility shift assays, and mutation of this element markedly decreased the ability of the TAFI promoter to be activated by dexamethasone. 相似文献
62.
Prothrombinase cleaves prothrombin at Arg(271) and Arg(320) to produce thrombin. The kinetics of cleavage of five recombinant prothrombins were measured: wild-type prothrombin (WT-II), R155A/R284A/R271A prothrombin (rMZ-II), R155A/R284A/R320A prothrombin (rP2-II), S525C prothrombin labeled with fluorescein (WT-II-F*), and R155A/R284A/R271A/S525C prothrombin labeled with fluorescein (rMZ-II-F*). rMZ-II and rP2-II are cleaved only at Arg(320) and Arg(271), respectively, to yield the intermediates meizothrombin and prethrombin-2, respectively. WT-II-F* and rMZ-II-F* were labeled at Cys(525) with fluorescein; cleavage was monitored by enhanced fluorescence. Activation kinetics of WT-II, rMZ-II, and rP2-II indicated that the catalytic efficiency of cleavage at Arg(320) was increased by 30,000-fold by the cofactor factor Va, as was the conversion of prothrombin to thrombin. However, factor Va increased cleavage at Arg(271) only by 34-fold. Although WT-II competitively inhibited cleavage of WT-II-F*, rMZ-II or rP2-II did not inhibit completely even at saturating concentrations. However, rMZ-II and rP2-II together inhibited WT-II-F* cleavage competitively. Both WT-II and rMZ-II competitively inhibited rMZ-II-F* cleavage, whereas rP2-II did not. A model of prothrombin activation that includes two equilibrating forms of prothrombinase, each recognizing one of the cleavage sites, is quantitatively consistent with all of the experimental observations. Therefore, we conclude that the kinetics of prothrombin activation can be described by a "ping-pong"-like mechanism. 相似文献
63.
Orfeo T Brufatto N Nesheim ME Xu H Butenas S Mann KG 《The Journal of biological chemistry》2004,279(19):19580-19591
The prothrombinase complex consists of the protease factor Xa, Ca2+, and factor Va assembled on an anionic membrane. Factor Va functions both as a receptor for factor Xa and a positive effector of factor Xa catalytic efficiency and thus is key to efficient conversion of prothrombin to thrombin. The activation of the procofactor, factor V, to factor Va is an essential reaction that occurs early in the process of tissue factor-initiated blood coagulation; however, the catalytic sequence leading to formation of factor Va is a subject of disagreement. We have used biophysical and biochemical approaches to establish the second order rate constants and reaction pathways for the activation of phospholipid-bound human factor V by native and recombinant thrombin and meizothrombin, by mixtures of prothrombin activation products, and by factor Xa. We have also reassessed the activation of phospholipid-bound human prothrombin by factor Xa. Numerical simulations were performed incorporating the various pathways of factor V activation including the presence or absence of the pathway of factor V-independent prothrombin activation by factor Xa. Reaction pathways for factor V activation are similar for all thrombin forms. Empirical rate constants and the simulations are consistent with the following mechanism for factor Va formation. alpha-Thrombin, derived from factor Xa cleavage of phospholipid-bound prothrombin via the prethrombin 2 pathway, catalyzes the initial activation of factor V; generation of factor Va in a milieu already containing factor Xa enables prothrombinase formation with consequent meizothrombin formation; and meizothrombin functions as an amplifier of the process of factor V activation and thus has an important procoagulant role. Direct activation of factor V by factor Xa at physiologically relevant concentrations does not appear to be a significant contributor to factor Va formation. 相似文献
64.
Schneider M Brufatto N Neill E Nesheim M 《The Journal of biological chemistry》2004,279(14):13340-13345
Activated thrombin-activable fibrinolysis inhibitor (TAFIa) is a carboxypeptidase B-like plasma enzyme that can slow clot lysis by removing lysine residues exposed on fibrin as it is cleaved by plasmin. Previously, it was shown that fibrin treated with TAFIa is less able to promote plasminogen activation by tissue-type plasminogen activator. In this study, the effect of TAFIa modification of a fibrin surface on the rate of plasmin inhibition by antiplasmin was studied using high molecular weight fibrin degradation products (HMw-FDPs) as a soluble model for intact plasmin-modified fibrin. To quantify the inhibition, a novel end point assay was employed where plasmin, antiplasmin, and cofactors were mixed in the presence of a chromogenic substrate and the end point in the substrate hydrolysis reaction was used to measure the second order rate constant of inhibition. When HMw-FDPs were titrated in the presence of plasmin and antiplasmin, the rate constant for inhibition decreased by 16-fold at saturation (9.6 x 10(6) m(-1) s(-1) to 0.59 x 10(6) m(-1) s(-1)). When HMw-FDPs were pretreated with TAFIa, nearly two-thirds of the protective effect was lost. When 730 nm HMw-FDPs were treated for 20 min with TAFIa, the rate constant for plasmin inhibition was increased 3-fold from 1.9 x 10(6) m(-1) s(-1) to 6.2 x 10(6) m(-1) s(-1). Therefore, a novel mechanism was identified whereby TAFIa can modulate plasmin levels by increasing the susceptibility of plasmin to inhibition by antiplasmin. 相似文献
65.
Previous work using soluble fibrin surrogates or very dilute fibrin indicate that inhibition of plasmin by antiplasmin is attenuated by fibrin surrogates; however, this phenomenon has not been quantified within intact fibrin clots. Therefore, a novel system was designed to measure plasmin inhibition by antiplasmin in real time within an intact clot during fibrinolysis. This was accomplished by including the plasmin substrate S2251 and a recombinant fluorescent derivative of plasminogen (S741C-fluorescein) into clots formed from purified components. Steady state plasmin levels were estimated from the rates of S2251 hydrolysis, the rates of plasminogen activation were estimated by fluorescence decrease over time, and residual antiplasmin was deduced from residual fluorescence. From these measurements, the second order rate constant could be inferred at any time during fibrinolysis. Immediately after clot formation, the rate constant for inhibition decreased 3-fold from 9.6 x 10(6) m(-1) s(-1) measured in a soluble buffer system to 3.2 x 10(6) m(-1) s(-1) in an intact fibrin clot. As the clot continued to lyse, the rate constant for inhibition continued to decrease by 38-fold at maximum. To determine whether this protection was the result of plasmin exposure of carboxyl-terminal lysine residues, clots were formed in the presence of activated thrombin-activatable fibrinolysis inhibitor (TAFIa). In the presence of TAFIa, the initial protective effect associated with clot formation occurred; however, the secondary protective effect associated with lysine residue exposure was delayed in a TAFIa concentration-dependent manner. This latter effect represents another mechanism whereby TAFIa attenuates fibrinolysis. 相似文献
66.
V?Srinivasan GJM?Maestroni DP?Cardinali AI?Esquifino SR?Pandi?Perumal SC?MillerEmail author 《Immunity & ageing : I & A》2005,2(1):17
Aging is associated with a decline in immune function (immunosenescence), a situation known to correlate with increased incidence
of cancer, infectious and degenerative diseases. Innate, cellular and humoral immunity all exhibit increased deterioration
with age. A decrease in functional competence of individual natural killer (NK) cells is found with advancing age. Macrophages
and granulocytes show functional decline in aging as evidenced by their diminished phagocytic activity and impairment of superoxide
generation. There is also marked shift in cytokine profile as age advances, e.g., CD3+ and CD4+ cells decline in number whereas
CD8+ cells increase in elderly individuals. A decline in organ specific antibodies occurs causing reduced humoral responsiveness.
Circulating melatonin decreases with age and in recent years much interest has been focused on its immunomodulatory effect.
Melatonin stimulates the production of progenitor cells for granulocytes-macrophages. It also stimulates the production of
NK cells and CD4+ cells and inhibits CD8+ cells. The production and release of various cytokines from NK cells and T-helper
lymphocytes also are enhanced by melatonin. Melatonin presumably regulates immune function by acting on the immune-opioid
network, by affecting G protein-cAMP signal pathway and by regulating intracellular glutathione levels. Melatonin has the
potential therapeutic value to enhance immune function in aged individuals and in patients in an immunocompromised state. 相似文献
67.
MCWHINNIE MARY A.; CAHOON MARY ODILE SR.; JOHANNECK ROSEMARIE 《Integrative and comparative biology》1969,9(3):841-855
Cyclic shifts of calcium in the exoskeleton and soft tissues,as they are related to the intermolt cycle in crayfish, arereviewed. Regulatory factors, derived from the eyestalk, influencelevels of exoskeletal calcium; eyestalk extracts prepared fromanimals in premolt decrease shell calcium, while reciprocallyextracts from animals in intermolt increase it when these hormonalsources are injected into animals in the premolt stage (D0-D4). In addition, premolt eyestalk extract results in an increasein gastrolith calcium. In the exchange of calcium between theanimal and its environment there is evidence for differentialdepositionof recently available calcium in the exoskeleton. Further, intermoltand early premolt animals maintained in Ca45-labelled waterfor 15 days concentrate it 4 and 3fold in the exoskeletonand stomach, respectively. However, removal of a molt-inhibitingfactor through ablation of eyestalks results in a 20 and 40foldincrease in incorporation inthese same sites relative to environmentalconcentrations. Treatment with mammalian parathyroid extract mobilizes bothexoskeletal and gastric calciumand leads to a rise in bloodcalcium. However, there is little or no effect on levels ofexoskeletal citric acid. Further, citric acid is higher in thecrayfish carapace during stage C, the period of mineralization,than in stage D, the period of demineralization. There are both similarities and differences between the effectsof crustacean and mammalianregulating factors with respect tothe direction and extent of mineralization. Biochemical studiesshould elucidate the mechanisms regulated by these hormones. 相似文献
68.
The partition matrix: exploring variable phylogenetic signals along nucleotide sequence alignments 总被引:6,自引:2,他引:4
The partition matrix is a graphical tool for comparative analysis of
nucleotide sequences following alignment. It is particularly useful for
investigating the divergent phylogenies of sequence regions undergoing
reticulate evolution. A partition matrix is generated by determining the
consistency of the parsimoniously informative sites in a set of aligned
sequences with the binary partitions inferred from the sequences. Since the
linear order of sites is maintained, the matrix can be used to assess
whether the distribution of sites either supporting or conflicting with
particular partitions changes along the length of the alignment. The
usefulness of the matrix in allowing visual identification of differences
in evolutionary history among regions depends on the order in which
partitions are shown; several suitable ordering schemes are proposed. We
demonstrate the use of the partition matrix in interpreting the evolution
of the pseudoautosomal boundary region on the sex chromosome of catarrhine
primates. Its routine use should help to avoid attempts to derive single
phylogenies from sequences whose evolution has been reticulate and to
identify the gene conversion or recombination events underlying the
reticulation. The method is relatively fast. It is exploratory, and it can
form the basis for more formal analysis, which we discuss.
相似文献
69.
Positive selection and sequence rearrangements generate extensive polymorphism in the gamete recognition protein bindin 总被引:27,自引:12,他引:15
Bindin is a gamete recognition protein of sea urchins that mediates
species-specific attachment of sperm to an egg-surface receptor during
fertilization. Sequences of bindin from closely related urchins show fixed
species-specific differences. Within species, highly polymorphic bindin
alleles result from point substitution, insertion/deletion, and
recombination. Since speciation, positive selection favoring allelic
variants has generated diversity in bindin polypeptides. Intraspecific
bindin variation can be tolerated by the egg receptor, which suggests
functional parallels between this system and other flexible recognition
systems, including immune recognition. These results show that polymorphism
in mate recognition loci required for rapid evolution of sexual isolation
can arise within natural populations.
相似文献
70.