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R J Flower

Publications and source records attributed to R J Flower.

At least 109 records · Page 6Linked to original sources
PubMed1995

Dexamethasone inhibits the release of TSH from the rat anterior pituitary gland in vitro by mechanisms dependent on de novo protein synthesis and lipocortin 1.

Glucocorticoids have been shown repeatedly to inhibit the secretion of TSH in experimental animals and in man but their site and mode of action are unknown. In the present study, we have used an in vitro model to examine the effects of dexamethasone on the resting and pharmacologically evoked secretion of TSH by the rat anterior pituitary gland, and to show how they are influenced by inhibitors of RNA/protein synthesis. In addition, we have investigated the potential role of lipocortin 1 (LC1), a protein shown previously to contribute to glucocorticoid action in several systems, as a mediator of the glucocorticoid-induced suppression of TSH release in our in vitro preparation. The significant (P < 0.01) increases in the release of immunoreactive (ir)TSH from rat anterior pituitary tissue initiated by submaximal concentrations of TRH (10 nmol/l), vasoactive intestinal polypeptide (VIP, 10 nmol/l) or the adenyl cyclase activator, forskolin (100 mumol/l) were reduced significantly (P < 0.05) by preincubation of the tissue with dexamethasone (0.1 mumol/l). In contrast, irTSH secretion evoked by a submaximal concentration of the L-Ca2+ channel opener BAY K8644 (10 mumol/l) was unaffected by the steroid, although readily antagonised (P < 0.01) by nifedipine (1-100 mumol/l). Inclusion of actinomycin D (1.78 mumol/l) or cycloheximide (0.8 mumol/l), inhibitors of RNA and protein synthesis respectively, in the medium effectively abrogated the inhibitory effects of dexamethasone (0.1 mumol/l) on the secretory responses to TRH (10 nmol/l), VIP (10 nmol/l) and forskolin (100 mumol/l). LC1 was readily detectable by Western blotting in protein extracts of freshly excised anterior pituitary tissue. A small proportion of the protein was found to be attached to the outer surface of the cells where it was retained by a Ca(2+)-dependent mechanism. Exposure of the tissue to dexamethasone (0.1 mumol/l) caused a pronounced increase in the amount of cellular LC1 attached to the outer surface of the cells and a concomitant decrease in the intracellular LC1 pool. Progesterone (0.1 mumol/l) and aldosterone (0.1 mumol/l) were also weakly active in this regard, but thyroxine and tri-iodothyronine (0.1 mumol/l) were not. Addition of an N-terminal LC1 fragment, LC1(1-188) (0.05-0.53 pmol/l) to the incubation medium reduced significantly (P < 0.01) the increases in irTSH release induced by TRH (10 nmol/l), VIP (10 nmol/l) and forskolin (100 mumol/l), but failed to influence (P < 0.05) those initiated by BAY K8644 (10 mumol/l). Furthermore, the inhibitory actions of dexamethasone (0.1 mumol/l) on the release of irTSH provoked by TRH (10 nmol/l), VIP (10 nmol/l) and forskolin (100 mumol/l) were substantially reversed (P < 0.01) by a specific monoclonal anti-LC1 antibody, while an isotype-matched control antibody was without effect. The results show clearly that dexamethasone, a semi-synthetic glucocorticoid, acts at the pituitary level to inhibit the neurochemically evoked release of irTSH. They also provide novel evidence that the inhibitory actions of the steroid are dependent upon de novo RNA/protein synthesis and that they involve an LC1 dependent mechanism.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1994

Antisense oligonucleotides to human lipocortin-1 inhibit glucocorticoid-induced inhibition of A549 cell growth and eicosanoid release.

Glucocorticoids actively inhibit the growth of A549 cells by suppressing the release of factors such as prostaglandin E2 (PGE2) necessary for their proliferation. This effect is largely mediated through induction of the protein lipocortin-1. We now show that transient transfection of A549 cells with an antisense DNA oligonucleotide targeted to a region coding the unique N-terminal portion of human lipocortin-1 blocks the induction of lipocortin-1 protein following glucocorticoid treatment and completely reverses glucocorticoid-induced suppression of cell proliferation and PGE2 release. A scrambled oligonucleotide was without effect. Continued culture of A549 cells in the presence of this oligonucleotide results in a sustained increase in cell proliferation and PGE2 release. This study reinforces the importance of lipocortin-1 as a negative modulator of cell growth and eicosanoid generation in this system.

Annexin A1↗
PubMed1994

Induction of lipocortin 1 by topical steroid in rat skin.

Western blotting and densitometric analysis of extracts obtained from EDTA extraction of skin segments showed greater extracellular Lipocortin 1 (LC1) in skin sites from steroid-treated animals compared to that seen in matched vehicle treated animals. Extracellular LC1 was maximal 3 hr after steroid, less was found in skin after 6 hr and levels had returned to basal at 18 hr. Pre-treatment of rats with the glucocorticoid receptor antagonist RU38486 (20 mg/kg) prevented the steroid induction of extracellular LC1 at both the 3 and 6 hr time-points. Systemic treatment of rats with betamethasone sodium phosphate (0.1-1 mg/kg) showed that the induction of LC1 on the cell surface was both time- and dose-dependent. Oedema in rat skin caused by 5-hydroxytryptamine (5-HT), platelet activating factor (PAF) and zymosan activated serum (ZAS) was assessed using 125I-labelled human serum albumin. Following a 3 hr topical treatment with betamethasone-17-valerate the inflammatory activities of all of the tested stimuli were significantly attenuated demonstrating that at this time-point the topical steroid was biologically active. Topical steroid treatment of the skin resulted in a translocation of LC1 to the cell surface, which was maximal after a 3 hr period and was also temporally associated with the anti-inflammatory effect of these agents.

Administration, Topical↗
PubMed1994

Dexamethasone suppression of IL-1 beta-induced cyclooxygenase 2 expression is not mediated by lipocortin-1 in A549 cells.

A549 cells grown under serum free conditions do not express cyclooxygenase 2 (cox 2). However, addition of IL-1 beta results in the induction of cox 2 in a time and dose dependent manner; actinomycin D completely blocks this induction. Dexamethasone completely suppressed the induction of cox 2 only if present during the first 3.5h of IL-1 beta treatment but not if added after 3.5h. Treatment with a neutralising monoclonal antibody (1A, Biogen) specific to lipocortin-1 failed to reverse this inhibition by dexamethasone. However, using this same antibody we were able to reverse completely the effects of dexamethasone on the suppression of PGE2 release. These observations support the idea that glucocorticoids directly regulate cox 2 expression at the transcriptional level and this phenomenon is not mediated by lipocortin-1.

Annexins↗
PubMed1994

Differential role of extra- and intracellular calcium in bradykinin and interleukin 1 alpha stimulation of arachidonic acid release from A549 cells.

The release of arachidonic acid in A549 cells was stimulated in a time- and dose-dependent manner by the Ca2+ ionophore ionomycin (t1/2 = 4 min), thapsigargin (t1/2 = 8 min), bradykinin (t1/2 = 12 min, EC50 = 3 nM), and interleukin 1 alpha (t1/2 = 28 min, EC50 = 0.3 ng/ml). Bradykinin (10 nM) and interleukin 1 alpha (1 ng/ml) stimulation was blocked by the bradykinin B2 receptor antagonist, D-Arg,[Hyp3,Thi5,8, D-Phe7]bradykinin and interleukin 1 receptor antagonist (IC50 = 30 mM and 20 ng/ml, respectively), suggesting receptor mediation. Diacylglycerol release was < 10% of total arachidonic acid release in all cases, suggesting activation of phospholipase A2 activity was greater than phospholipase C activation by these agents. The effects of ionomycin (3 microM) and thapsigargin (0.3 microM) were abolished in Ca(2+)-free buffer with and without 0.5 mM EGTA. Bradykinin (10 nM) stimulation was reduced by 50% in Ca(2+)-free buffer whereas interleukin 1 alpha (1 ng/ml) stimulation remained unaffected. However, the presence of EGTA completely abolished bradykinin stimulation and partially blocked the effect of interleukin 1 alpha (43% inhibition). In the presence of extracellular Ca2+, ionomycin (3 mM), thapsigargin (0.3 mM), bradykinin (10 nM), and interleukin 1 alpha (1 ng/ml) stimulation of arachidonic acid release was blocked by the Ca2+ influx blocker LaCl3 (29, 44, 35, and 41% inhibition, respectively). Nifedipine also blocked ionomycin and thapsigargin stimulation but only partially blocked bradykinin and interleukin 1 alpha stimulation. These results suggest that following B2 receptor activation, cytosolic phospholipase A2 is stimulated by a rise in intracellular Ca2+ levels which are sensitive to the action of EGTA, whereas interleukin 1 alpha stimulation of cytosolic phospholipase A2 is mediated by a rise in intracellular Ca2+ from both EGTA-sensitive and resistant pools. Furthermore the results of ionomycin and thapsigargin indicate that extracellular Ca2+ is important for activation of cytosolic phospholipase A2 in A549 cells.

Arachidonic Acid↗
PubMed1994

Tamoxifen inhibits growth of oestrogen receptor-negative A549 cells.

The non-steroidal anti-oestrogen tamoxifen inhibits proliferation of the A549 human lung adenocarcinoma cell line (EC50 congruent to 10 nM) yet there was no evidence of oestrogen receptor expression as determined by ligand binding assay and northern blotting. 17-beta-Oestradiol had no effect on A549 cell proliferation (1 pM-1 microM) and moreover a 100-fold excess failed to reverse the effect of 10 nM tamoxifen as did a 100-fold excess of the steroidal anti-oestrogens ICI 164384 and ICI 182780. However, 4-hydroxytamoxifen which had no significant effect on A549 cell growth (1 pM-1 microM) completely antagonized the effect of 10 nM tamoxifen when used at a 100-fold excess. In the presence of oleic acid and stearic acid (10 microM) the growth inhibitory effect of tamoxifen in A549 cells was greatly enhanced, unlike effects mediated by the anti-oestrogen binding protein described in other cells where these fatty acids had no effect. These results indicate the presence of a unique and highly sensitive mechanism in A549 cells whereby concentrations of tamoxifen relevant to classical receptor binding can inhibit cell growth in the absence of the oestrogen receptor.

Cell Division↗
PubMed1994

Lipocortin-1: cellular mechanisms and clinical relevance.

Lipocortin-1, a 37 kDa member of the annexin superfamily of proteins, originally evoked interest as one of the 'second messengers' of the anti-inflammatory actions of the glucocorticoids. Subsequent research has shown that the protein plays a major regulatory role in systems as diverse as cell-growth regulation and differentiation, neutrophil migration, CNS responses to cytokines, neuroendocrine secretion and neurodegeneration. The role of lipocortin-1 in mediating glucocorticoid-induced effects in these systems has been demonstrated using immunoneutralization strategies and by mimicking steroid actions with highly purified or recombinant lipocortin-1 or its biologically active peptide fragments. Originally the mode of action of lipocortin-1 seemed to be largely through inhibition of prostaglandin formation, but it is now clear that it can modify other aspects of cell function, perhaps pointing to a more fundamental mechanism than was originally envisaged. In this article Rod Flower and Nancy Rothwell review the nature, possible mechanisms and clinical relevance of these diverse actions of lipocortin-1.

Animals↗
PubMed1994

Cytokines, glucocorticoids and neuroendocrine function.

Activation of the immune system is normally associated with widespread alterations in neuroendocrine activity, the profile of which depends upon the species and on the severity and duration of the stimulus. Particularly important in this regard is the activation of the hypothalamo-pituitary-adrenocortical (HPA) axis for the consequent rise in circulating glucocorticoids serves to contain the ensuing pathophysiological responses and thus to restore homeostasis. In the present study, in vivo and in vitro techniques have been used to examine the influence of various immunokines on the HPA axis and to determine whether their actions are modulated by glucocorticoids and lipocortin 1 (LC1). In vivo interleukin-1 beta (IL-1 beta), given orally or peripherally, produced increases (P < 0.01) the serum corticosterone concentration which were reversed by pretreatment with dexamethasone. IL-1 beta also produced glucocorticoid reversible increases in the release of the two corticotrophin releasing factors, CRF-41 and AVP, from the hypothalamus in vitro (P < 0.01) as also did IL-1 alpha, IL-6 and IL-8. By contrast, none of these cytokines influenced directly the release of ACTH from pituitary tissue in vitro. The inhibitory actions of the glucocorticoids on the HPA responses to cytokines observed in vivo and in vitro were mimicked by LC1 and reversed by neutralizing anti-LC1 antisera. Our results demonstrate a role of cytokines, glucocorticoids and LC1 in effecting the interplay between the brain-neuroendocrine and immune system which may be critical to host defence in conditions of both health and disease.

Animals↗
PubMed1994

Cytokines, glucocorticoids and lipocortins in the control of neutrophil migration.

By using a simple murine air-pouch technique we were able to measure an intense neutrophil infiltration in response to the local application of specific pro-inflammatory stimuli such as interleukin-1 and interleukin-8. The role of endogenous and exogenous lipocortin 1 on this cellular migratory response was evaluated. Exogenously i.v. administration of human recombinant lipocortin 1 and its N-terminus peptide Ac2-26 dose-dependently inhibited IL-1-induced neutrophil migration with calculated ED50 values of 5.18 +/- 0.74 micrograms and of 88.0 +/- 13.1 micrograms per mouse, respectively. Direct injection of these agents into the pouch was ineffective. In keeping with these observations, the inhibitory action exerted by dexamethasone, in both IL-1- and IL-8-induced cell infiltration, was abrogated by passive immunisation of mice with specific anti-lipocortin 1 antibodies. In conclusion, lipocortin 1 is not only a mediator of some of the anti-inflammatory actions of glucocorticoid hormones, but can also modulate the effect that specific cytokines have on the trafficking of highly specialised cells like the neutrophils.

Animals↗
PubMed1994

A role for endogenous histamine in interleukin-8-induced neutrophil infiltration into mouse air-pouch: investigation of the modulatory action of systemic and local dexamethasone.

1. When injected into a 6-day-old mouse air-pouch, human recombinant interleukin-8 (IL-8; 0.03-3 micrograms) induced, in a dose-dependent fashion, an accumulation of neutrophils which could be reliably assessed 4 h after the injection. No protein extravasation was measured above the values obtained with the vehicle alone (carboxymethylcellulose, CMC, 0.5% w/v in phosphate-buffered solution, PBS). 2. The IL-8 effect (routinely evaluated at 1 microgram dose) was inhibited neither by local administration of actinomycin D (1 microgram) nor by systemic treatment with indomethacin (1 mg kg-1, i.v.), BWA4C (5 mg kg-1, p.o.), methysergide (6 mg kg-1, i.p.) and RP67580 (2 mg kg-1, i.p.). 3. Treatment of mice with the H1 antagonist, mepyramine (1-10 mg kg-1, i.p.) resulted in a dose-dependent inhibition of the cell accumulation elicited by the chemokine, with a maximal reduction of approximately 50-60%. The mepyramine effect was not due to a non specific reduction of neutrophil function, since treatment with this drug (6 mg kg-1, i.p.) did not modify the cell infiltration measured in response to a challenge with interleukin-1 beta (20 ng) or with the vehicle CMC to any extent. Moreover, treatment of mice with mepyramine did not modify cell counts in a peripheral blood film with respect to controls. Two other H1 antagonists, chemically unrelated to mepyramine, diphenhydramine (9 mg kg-1, i.p.) and triprolidine (0.5 mg kg-1, i.p.), inhibited IL-8-induced migration to a similar extent (approximately 50-60%), whereas the H2 antagonist, ranitidine (5 mg kg-1, i.p.) was without effect. 4. The concept that endogenous histamine could be involved in the IL-8 effect was strengthened in two ways: (i) addition of histamine (0.2-2 microg) to a small dose of IL-8 (0.3 microg) potentiated the cell elicitation induced by the chemokine without having any effect on its own; (ii) IL-8-induced neutrophil accumulation was greatly impaired in animals depleted of mast cell amines by sub-chronic (5 day) treatment with compound 48/80 according to an established protocol.5. The glucocorticoid dexamethasone (Dex; 1-50 microg per mouse, i.v., corresponding approximately to 0.03-1.5 mg kg-1, given i.v. 2 h prior to challenge with IL-8) potently inhibited neutrophil infiltration with an approximate ED50 of 5 microg per mouse (~ 0.3 mg kg-1 , i.v.). Passive immunisation of mice with a polyclonal sheep serum raised against the steroid-inducible anti-inflammatory protein lipocortin 1 (LCl)abolished the inhibitory action of Dex whereas a control serum was without effect.6. Local administration of Dex at a dose which was ineffective when given systemically (1 microg) also reduced neutrophil migration induced by IL-8, either alone or in combination with histamine. This local inhibition (~50%), also seen with hydrocortisone (30 microg), was prevented by the concomitant administration of the steroid antagonist RU38486 (10 microg) indicating the involvement of glucocorticoid receptor in the response.7. These findings characterize further the mechanisms underlying PMN recruitment induced by IL-8 in vivo, and point to a role for histamine. The anti-inflammatory action of the glucocorticoids, as in some other models, appears to be LCl-dependent when these drugs are given systemically and LCl independent when the steroids are given locally.

Adjuvants, Immunologic↗
PubMed1994

Circulating group II phospholipase A2 activity and antilipocortin antibodies in systemic lupus erythematosus. Correlative study with disease activity.

OBJECTIVE: Lipocortin (LC) and phospholipase A2 (PLA2) are involved in phospholipid metabolism, and on the cellular level LC seems to be an antagonist of PLA2. Since anti-LC1 autoantibodies were found in systemic lupus erythematosus (SLE), we undertook a study of the relationship between PLA2, anti-LC1, and disease activity in a large group of patients with SLE. METHODS: Sera from 81 patients with SLE were tested for the activity of extracellular PLA2 and the presence and level of antilipocortin 1 [anti-LC1 (IgM) and anti-LC1 (IgG)] antibodies. Both were compared to SLE activity. RESULTS: Mean PLA2 activity was 4.6-fold higher in patients with SLE than in healthy controls (707 +/- 219 vs 154 +/- 6 u/ml, p < 0.01). PLA2 activity correlated significantly with PLA2 immunoreactivity as estimated by an ELISA method using monoclonal antibodies against "synovial type" PLA2 (n = 21, r = 0.984, p < 0.001). Anti-LC1 IgM and IgG antibody levels were significantly higher in SLE than in healthy individuals [anti-LC1 (IgM) 54.5 +/- 4.6 vs 22.6 +/- 2.3 EU/ml, p < 0.001 and anti-LC1 (IgG) 54.3 +/- 3.4 vs 22.9 +/- 2.3 EU/ml, p < 0.001]. There was no correlation between PLA2 activity and anti-LC1 antibody titers. Elevated levels of PLA2 [> normal mean + 2 SD (i.e., > 300 u/ml)] were found in 41/81 patients with SLE. Anti-LC1 antibody titers were high (> 64 EU/ml) in 23/41 patients; 14/40 patients with SLE with normal PLA2 (< 300 u/ml) also had higher titers of anti-LC1 antibodies. PLA2 activity was significantly associated with the presence of synovitis, being markedly increased in 11/12 patients. Mean PLA2 in this group of patients (1593 +/- 957 u/ml) was significantly higher (p < 0.001) than that (553 +/- 188 u/ml) in the group of 69 patients with SLE without synovitis. CONCLUSIONS: There was no correlation of PLA2 activity with the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) or the Lupus Activity Criteria Count (LACC). Circulating PLA2 activity in SLE correlated only with active synovitis. There was no correlation of anti-LC1 titers with duration of the disease, age, steroid dosage, SLEDAI, or LACC or any individual clinical or laboratory variable included in the assessment of SLEDAI and LACC.

Adult↗
PubMed1993

Selectivity of nonsteroidal antiinflammatory drugs as inhibitors of constitutive and inducible cyclooxygenase.

Constitutive cyclooxygenase (COX-1; prostaglandin-endoperoxide synthase, EC 1.14.99.1) is present in cells under physiological conditions, whereas COX-2 is induced by some cytokines, mitogens, and endotoxin presumably in pathological conditions, such as inflammation. Therefore, we have assessed the relative inhibitory effects of some nonsteroidal antiinflammatory drugs on the activities of COX-1 (in bovine aortic endothelial cells) and COX-2 (in endotoxin-activated J774.2 macrophages) in intact cells, broken cells, and purified enzyme preparations (COX-1 in sheep seminal vesicles; COX-2 in sheep placenta). Similar potencies of aspirin, indomethacin, and ibuprofen against the broken cell and purified enzyme preparations indicated no influence of species. Aspirin, indomethacin, and ibuprofen were more potent inhibitors of COX-1 than COX-2 in all models used. The relative potencies of aspirin and indomethacin varied only slightly between models, although the IC50 values were different. Ibuprofen was more potent as an inhibitor of COX-2 in intact cells than in either broken cells or purified enzymes. Sodium salicylate was a weak inhibitor of both COX isoforms in intact cells and was inactive against COX in either broken cells or purified enzyme preparations. Diclofenac, BW 755C, acetaminophen, and naproxen were approximately equipotent inhibitors of COX-1 and COX-2 in intact cells. BF 389, an experimental drug currently being tested in humans, was the most potent and most selective inhibitor of COX-2 in intact cells. Thus, there are clear pharmacological differences between the two enzymes. The use of such models of COX-1 and COX-2 activity will lead to the identification of selective inhibitors of COX-2 with presumably less side effects than present therapies. Some inhibitors had higher activity in intact cells than against purified enzymes, suggesting that pure enzyme preparations may not be predictive of therapeutic action.

Animals↗
PubMed1993

Lipocortin-1 fragments inhibit neutrophil accumulation and neutrophil-dependent edema in the mouse. A qualitative comparison with an anti-CD11b monoclonal antibody.

The activity of the steroid-inducible protein lipocortin-1 (LC1; with a primary sequence of 346 amino acids; also called annexin 1), a fragment corresponding to amino acids 1-188 and a short peptide from the N-terminus (amino acid 2-26) were tested for anti-inflammatory actions in three models of acute inflammation in the mouse in comparison with a mAb anti-CD11b (alpha CD11b). In the mouse air-pouch model LC1, fragment 1-188 and peptide Ac2-26 exhibited powerful inhibitory effects (ED50 approximately 5.2, 38 and 88 micrograms/mouse, respectively) on leukocyte migration elicited by IL-1. LC1 was approximately 200 times more potent than Ac2-26 on a molar basis although both gave maximal inhibitions, in contrast fragment 1-188 only produced a partial dose-response curve. LC1 was approximately 20 times more potent on a molar basis in this assay than the alpha CD11b mAb. Peptide Ac2-26 and the mAb alpha CD11b also blocked cell migration into the air-pouch induced by IL-8 with approximately the same potency. In the mouse skin edema and zymosan peritonitis assays Ac2-26 was inhibitory (ED50 of 200 micrograms/mouse) but less so than the alpha CD11b antibody (ED50 approximately 0.5 mg/mouse). Both LC1 (10 micrograms) and Ac2-26 (200 micrograms) completely blocked FMLP-induced neutropenia in the mouse. Studies using an inactivated LC1 preparation, which binds to the same high affinity binding sites as the biologically active material, indicated that the short peptide acts on the same sites as the native LC1. This study confirms the activity of LC1 in another model of experimental inflammation and suggests that it acts partly through inhibition of leukocyte activation with an overall effect qualitatively comparable to the blocking of CD11b portion of a beta 2-integrin complex. It also shows that peptides derived from the N-terminal domain of LC1 may mimic the activity of the full length molecule and points the way for a new family of anti-inflammatory substances that inhibit leukocyte trafficking.

Amino Acid Sequence↗
PubMed1993

Phospholipase A2-induced stimulation of A549 lung adenocarcinoma cell line proliferation.

Phospholipase A2 (PLA2) activity was found in the cytosolic fraction of the A549 human lung adenocarcinoma line. This PLA2 had a molecular mass of approximately 70 kDa as assessed by gel filtration chromatography and required submicromolar concentrations of calcium concentrations for optimal activity. These characteristics are consistent with the cytosolic PLA2 recently reported in other cell types, such as U937 cells. We have now demonstrated that A549 cell PLA2 (PLA2 activity: 1 unit/ml) partially purified by gel filtration stimulated proliferation of A549 cells by 50% after 3 days of culture. Similarly, porcine pancreatic PLA2 (0.1 unit/ml) also promoted proliferation of A549 cell cultures by 42%. Furthermore, A549 cell PLA2 stimulated prostaglandin E2 release (approx. 7-fold increase). Both PLA2s lost activity when treated with p-bromophenacyl bromide. Neither porcine pancreatic PLA2 nor A549 cell PLA2 reversed the inhibitory activities of dexamethasone and indomethacin on cell growth. These results suggest that both of these PLA2s stimulate A549 cell growth, and that this is likely to be mediated by increased eicosanoid production.

Acetophenones↗
PubMed1993

The ability of murine leukocytes to bind lipocortin 1 is lost during acute inflammation.

Lipocortin 1, a member of the annexin superfamily of calcium and phospholipid binding proteins, mediates some of the anti-inflammatory actions of the glucocorticoid hormones. Lipocortin 1 binds to the surface of murine peripheral blood monocytes and polymorphonuclear leukocytes (Kd estimate 2 x 10(-8) M) but not lymphocytes. Resident peritoneal macrophages exhibit binding (Kd estimate 1.3 x 10(-8) M) but lymphocytes do not. A 95-98% reduction in lipocortin 1 binding was observed to leukocytes obtained from air pouch or peritonitis models of inflammation. When given intravenously, lipocortin 1 binds rapidly to murine leukocytes within 5 min but disappears before 10 min, leaving the binding capacity of the cells unaltered. Modulation of lipocortin 1 binding sites could be an important step in regulating the function of inflammatory cells.

Animals↗
PubMed1993

N-terminal peptide fragments of lipocortin-1 inhibit A549 cell growth and block EGF-induced stimulation of proliferation.

Lipocortin-1 mediates growth inhibition of glucocorticoids in A549 cells by suppressing the release of PGE2 necessary for their proliferation. We now show that 2 peptide fragments derived from the N-terminal portion of lipocortin-1 corresponding to amino-acids 13-25 and 21-33 also inhibited A549 cell growth and suppressed release of PGE2, whereas peptides 1-12 and 13-25 (Phe21; in which the tyrosine at position 21 was replaced by a phenylalanine residue) were inactive. Similarly, peptide 21-33 (Phe21) and a scrambled sequence of 13-25 failed to inhibit cell growth. Moreover, the EGF-induced stimulation of cell proliferation and PGE2 release in these cells was blocked by peptides 13-25 and 21-33, and also by peptides 1-12, 13-25 (Phe21) and 21-33 (Phe21), but not by a scrambled sequence of peptide 13-25.

Adenocarcinoma↗