Lipocortin-1 is an endogenous inhibitor of ischemic damage in the rat brain.

Relton, Jane K.; Strijbos, Paul J. L. M.; O’Shaughnessy, Celestine T.; Carey, Frank; Forder, Robert A.; Tilders, F. J. H.; Rothwell, Nancy J.

doi:10.1084/jem.174.2.305

Cited by 133 publications

(61 citation statements)

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“…61 This reduction in infarct size is accompanied by a decreased number of leukocytes in the ischemic hemisphere and improved neurological function. 62 Similar results have been achieved by means of the topical application of anti-IL-1␤ neutralizing antibody, 53 zinc protoporphyrin, 53,60,63 and fragments of lipocortin-1, 58 all of which act as IL-1 inhibitors. TGF-␤ administration has led to less severe histological damage in a rabbit model of embolic stroke 100 as well as in rats subjected to permanent MCA occlusion, 101 transient global ischemia, 104 and hypoxia-ischemia cerebral insult.…”

Section: Experimental Anti-leukocyte Interventionssupporting

confidence: 63%

Cytokines and Cell Adhesion Molecules in Cerebral Ischemia

Pantoni

Sarti

Inzitari

1998

ATVB

125

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Abstract-The possibility of reopening an occluded cerebral artery by means of thrombolysis has renewed interest in a number of the several mechanisms that are active during acute cerebral ischemia. Over recent years, it has become apparent that leukocytes play a central role not only during the healing stage of brain infarction but also during the early phases of cerebral ischemia, when it is postulated that these cells produce harmful effects, particularly in the presence of reperfusion. This review is based on the critical analysis of more than 150 publications dealing with the role of leukocytes and some inflammatory mediators (cytokines, chemokines, and adhesion molecules) in cerebral ischemia. Animal studies indicate that leukocyte involvement is promoted by a variety of inflammatory molecules produced immediately after the onset of cerebral ischemia. Considerable experimental evidence suggests that these mediators play a key role in the progression from ischemia to irreversible injury (ie, cellular death and necrosis). However, the precise role of each molecule alone remains to be further elucidated as well as in relation to the complex network existing among different mediators. Progress in our understanding of the inflammatory mechanisms operating in cerebral ischemia has enabled the testing of new compounds with promising results in animals; in contrast, one recent controlled trial of an anti-leukocyte molecule in acute stroke patients showed negative results. This discrepancy may derive in part from our incomplete understanding of the complexity of the inflammatory mechanisms involved in cerebral ischemia. Our analysis suggests that until sufficient knowledge of the underlying disease mechanisms is acquired, more care should be taken when testing new and potentially efficacious drugs in stroke patients.

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Section: Experimental Anti-leukocyte Interventionssupporting

confidence: 63%

Cytokines and Cell Adhesion Molecules in Cerebral Ischemia

Pantoni

Sarti

Inzitari

1998

ATVB

125

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“…Besides, a new cerebral anti-ischemic activity has recently been reported in rat for the N-terminal LC-1 fragment 1-188 [13].…”

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confidence: 99%

Structural characterization of a biologically active human lipocortin 1 expressed in Escherichia coli

Arcone

Arpaia

Ruoppolo³

et al. 1993

European Journal of Biochemistry

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Lipocortin or annexin 1 is a calcium-dependent phospholipid-binding protein which probably acts as a glucocorticoid-regulated anti-inflammatory factor. cDNA for human lipocortin 1 was cloned in the pT7.7 expression plasmid under the control of the inducible bacteriophage T7 RNA polymerase promoter. Upon induction with isopropyl thio-p-D-galactoside, large amounts of the protein were produced and accumulated in Escherichia coli in a soluble form. The recombinant protein was purified to homogeneity by means of two subsequent ion-exchange chromatographic steps. The final yield was about 30 mg/l bacterial culture. Electrospray mass spectrometric analysis of the purified protein demonstrated that the recombinant product corresponds to the native human lipocortin 1, without the initial methionine and with a free N-terminal alanine; tryptic peptide mapping by fast-atom-bombardment mass spectrometry showed that the recombinant protein contains cysteine residues at positions 263 and 324 with free thiol groups, whereas Cys270 and Cys343 are probably involved in an intrachain disulfide bridge. Recombinant human lipocortin 1 reduces the carrageenininduced paw oedema in rat in vivo and inhibits porcine pancreatic phospholipase Az activity in vitro; in both cases, a dose-related response is observed.The lipocortin (LC) or annexin family includes structurally and immunologically related calcium and phospholipid-binding proteins, initially described for their anti-inflammatory properties [l, 21. These proteins are widely distributed in nature between and within species and are involved in several different calcium-mediated physiological and biochemical processes [3]. Up to now, 11 different annexin members have been identified [4, 51; LC-1 was initially purified from rat [6] and the corresponding human cDNA was cloned [7].Human LC-1 is a 38-kDa protein with a 33-kDa core, responsible of Ca2 + and phospholipid binding, linked to an Nterminal region consisting of 43 amino acids [2] which includes tyrosine and serine residues which are substrates for epidermal growth factor, tyrosine kinase receptor [8] and protein kinase C [9]. This suggests the involvement of LC-1 also as a mediator for intracellular signal transduction. Interestingly, phosphorylation occurring in the LC-1 N-terminal region have been found to alter Ca2+-dependent phospholipid-binding affinity of the core region [lo]. Other biological functions such as inhibition of synthesis and release of prolactin from human decidual cells [l 11, macrophage-mediated suppression in Correspondence to R. Arcone, CEINGE, Dipartimento di Biochimica e Biotecnologie Mediche, Universita di Napoli Federico 11, Via S. Pansini 5,I-80131 Napoli, ItalyAbbreviations. ES/MS, electrospray mass spectrometry ; FAB-MS, fast-atom-bombardment mass spectrometry; IPTG, isopropyl thio-jl-D-galactoside; LC-1, lipocortin 1 ; rhLC-1, recombinant human lipocortin 1 ; PLA2, phospholipase A,; NbsZ, 5,5'-dithiobis(2-nitrobenzoic acid).tumor-bearing mice have been described [12]. Besides, a new cerebral anti...

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“…Since that time, the molecule has been reported to have a variety of effects which, if true, would identify it as a major protein mediator of the anti-inflammatory actions of the glucocorticoids (4-9). For example, recombinant human lipocortin-I markedly inhibited the inflammatory process in the rat paw edema test (4) and in a model ofreperfusion injury in the rat brain (7). Furthermore, when added to leukocytes in vitro, lipocortin-I mimicked many of the effects ofglucocorticoids, including inhibition of erythrocyte-antibody rosette formation (8), superoxide generation (9), chemotaxis (5), and production of prostaglandin E 2 and leukotriene B 4 (6).…”

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confidence: 99%

“…Slow acetylation in humans is due to mutations in the single coding exon of the NAT2 gene (7). Mutant alleles Ml , M2, and M3 have thus far been identified, and individuals with the genotypes Ml/Ml, Ml/M2, Ml/M3, M2/M2, M2/ M3, and M3/M3 become slow acetylators (7).…”

mentioning

confidence: 99%

“…Mutant alleles Ml , M2, and M3 have thus far been identified, and individuals with the genotypes Ml/Ml, Ml/M2, Ml/M3, M2/M2, M2/ M3, and M3/M3 become slow acetylators (7). Using the nested polymerase chain reaction (PCR) (8) and subsequent restriction enzyme digestion, we investigated the association between the NAT2 genotypes and susceptibility to idiopathic SLE.…”

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confidence: 99%

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