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PubMed1996

S100 protein CP-10 stimulates myeloid cell chemotaxis without activation.

Leukocyte recruitment to inflammatory foci is generally associated with cellular activation. Recent evidence suggests that chemotactic agents can be divided into two classes, "classical chemoattractants" such as FMLP, C5a, and IL-8, which stimulate directed migration and activation events and "pure chemoattractants" such as TGF-beta 1 which influence actin polymerisation and movement but not oxidative burst and associated granular enzyme release. The studies reported here demonstrate that the murine S100 chemoattractant protein, CP-10, belongs to the "non-classical" group. Despite its potent chemotactic activity for neutrophils and monocytes/macrophages, CP-10 failed to increase [Ca2+]i in human or mouse PMN, although chemotaxis was inhibited by pertussis toxin, confirming the suggestion of a novel Ca(2+)-independent G-protein-coupled pathway for post-receptor signal transduction triggered by "pure chemoattractants." The co-ordinated up-regulation of Mac-1 and down-regulation of L-selectin induced by FMLP on human PMN in vitro was not observed with CP-10. Quantitative changes in immediate (30 s) actin polymerisation occurred with FMLP and CP-10-treated human PMN. The relative F-actin increases induced in WEHI 265 monocytoid cells by FMLP and CP-10 was optimal at 60 s and declined over 120 s. F-actin changes reflected the concentration and potencies of the agonists required to provoke chemotaxis. After 90 min, CP-10 profoundly altered cell shape and increased both cell size and F-actin within pseudopodia. These changes are typical of those mediating leukocyte deformability, and CP-10 may mediate leukocyte retention within microcapillaries and thereby contribute to the initiation of inflammation in vascular beds.

Actins↗
PubMed2005

Airway smooth muscle cells enhance C3a-induced mast cell degranulation following cell-cell contact.

Growing evidence suggests that anaphylatoxins, C3a and C5a, play important roles in innate immunity and may also participate in the pathogenesis of asthma. Previous studies with animal models and immunohistochemistry analysis of lung tissue indicated that anaphylatoxins may regulate airway hyperresponsiveness (AHR) in asthma via the activation of their cell surface G protein-coupled receptors (C3aR and C5aR) in airway smooth muscle (ASM) cells. Using RT-PCR, flow cytometry, and confocal microscopy, we made the surprising observation that while C3aR and C5aR were expressed in human mast cells, they were not present in cultured primary human or murine ASM cells. Furthermore, we could not detect C3aR in smooth muscle-positive cells of human trachea or bronchus. Interestingly, incubation of human mast cells with ASM cells, but not its culture supernatant, caused a significant enhancement of C3a-induced mast cell degranulation. Although stem cell factor (SCF) and its receptor c-kit are constitutively expressed on ASM cells and mast cells, respectively, neutralizing antibodies to SCF and c-kit failed to inhibit ASM cell-mediated enhancement of mast cell degranulation. However, dexamethasone-treated ASM cells were normal for cell surface SCF expression but were significantly less effective in enhancing C3a-induced mast cell degranulation when compared with untreated cells. These findings suggest that cell-cell interaction between ASM cells and mast cells, via a SCF-c-kit-independent but dexamethasone-sensitive mechanism, enhances C3a-induced mast cell degranulation, which likely regulates ASM function, thus contributing to the pathogenesis of asthma.

Animals↗
PubMed2006

Complement: a novel factor in basal and ischemia-induced neurogenesis.

Through its involvement in inflammation, opsonization, and cytolysis, the complement protects against infectious agents. Although most of the complement proteins are synthesized in the central nervous system (CNS), the role of the complement system in the normal or ischemic CNS remains unclear. Here we demonstrate for the first time that neural progenitor cells and immature neurons express receptors for complement fragments C3a and C5a (C3a receptor (C3aR) and C5a receptor). Mice that are deficient in complement factor C3 (C3(-/-)) lack C3a and are unable to generate C5a through proteolytic cleavage of C5 by C5-convertase. Intriguingly, basal neurogenesis is decreased both in C3(-/-) mice and in mice lacking C3aR or mice treated with a C3aR antagonist. The C3(-/-) mice had impaired ischemia-induced neurogenesis both in the subventricular zone, the main source of neural progenitor cells in adult brain, and in the ischemic region, despite normal proliferative response and larger infarct volumes. Thus, in the adult mammalian CNS, complement activation products promote both basal and ischemia-induced neurogenesis.

Animals↗
PubMed1993

Agonist-stimulated Cl- efflux from human neutrophils. A common phenomenon during neutrophil activation.

When human peripheral blood neutrophils were stimulated with various agonists which activate and/or prime neutrophils, we found that Cl- efflux was enhanced with a dramatic (50%) loss of intracellular Cl-. Interestingly, the Cl- efflux was enhanced by both agonists which induce a rapid transient increase in intracellular Ca2+ concentration ([Ca2+]i) [class I, e.g. N-formyl-methionyl-leucyl-phenylalanine (fMLP), interleukin-8 (IL8), platelet-activating factor, leukotriene B4 and C5a] and those which do not induce such an [Ca2+]i elevation [class II, e.g. tumor necrosis factor alpha (TNF) and granulocyte-macrophage colony-stimulating factor (GM-CSF)]. The time course of agonist-stimulated Cl- efflux differed depending on the agonist. Class I agonists such as IL8 and fMLP exhibited a 1 min lag phase before the onset of Cl- efflux; class II agonists such as GM-CSF and TNF displayed a 2 and 5 min lag phase, respectively. Both IL8 (class I)- and TNF (class II)-stimulated Cl- efflux exhibited similar sensitivity to inhibition by different types of ion transport inhibitors [ethacrynic acid (EA), amiloride, 4-acetamido-4'-isothiocyanatostilbene-2,2'-disulfonic acid, anthracene-9-carboxylic acid, and 4-4'-diisothiocyanatostilbene-2,2'-disulfonic acid]. On the other hand, natural Cl- efflux, which is thought to be mainly mediated by Cl-/Cl- self exchange, was not inhibited by EA (0.5 mM) or amiloride (0.3 mM). These results imply that both class I and class II agonist-stimulated Cl- efflux occurs via a common Cl- transporter which is different from that reported previously in resting human neutrophils. Although all agonists which induced a Cl- efflux also induced shape change of neutrophils, there did not appear to be a causal relationship between shape change and agonist-stimulated Cl- efflux. However, a temporal correlation was found to exist between agonist-stimulated Cl- efflux and intracellular alkalinization following agonist stimulation. Agonist-stimulated Cl- efflux therefore seems to be a common phenomenon activated by several agonists which act through different signal transduction pathways.

Biological Transport↗
PubMed1989

Differential release of mediators from human basophils: differences in arachidonic acid metabolism following activation by unrelated stimuli.

We have examined the release of histamine and LTC4 from purified human basophils challenged with several different stimuli, both physiological and nonphysiological. Basophils (n = 16) challenged with 0.1 micrograms/ml anti-IgE released 38 +/- 4% of their available histamine and 39 +/- 12 ng LTC4/10(6) basophils within 15-30 min. F-Met peptide (n = 8) caused the release of 54 +/- 8% histamine and 42 +/- 25 ng LTC4/10(6) basophils within a period of 2-5 min. C5a caused the release of 22 +/- 3% histamine from selected donors but failed to initiate any LTC4 release unless combined with D2O or 5 mM extracellular calcium. The two nonphysiological stimuli A23187 and TPA caused extensive histamine release, 67 +/- 8 and 82 +/- 11%, respectively, and while A23187 initiated a large and rapid release of leukotriene, TPA failed to release any LTC4 even when combined with D2O or 2-5 mM extracellular calcium. Increased concentrations of extracellular calcium enhanced anti-IgE and f-Met peptide induced release of LTC4 but inhibited the A23187 induced release of leukotriene. A single peak of immunoreactive leukotriene C4 that comigrated with the authentic standard was identified using HPLC followed by radioimmunoassay. No LTD4 or LTE4 could be detected. Purified human basophils incubated with 0.2 microM [3H]AA incorporated 290 pmol/10(6) cells, or 32 +/- 5% of the available label within 60 min. The [3H]AA was taken principally into the phospholipids (73 +/- 5%), with 20 +/- 3% as neutral lipid, and only 5 +/- 2% remaining as the free acid. Three phospholipid subclasses, phosphatidylcholine, PC (24 +/- 2%), phosphatidylinositol, PI (22 +/- 1%), and phosphatidylethanolamine, PE (15 +/- 3%), accounted for the majority of the incorporated [3H]AA while the remainder of the phospholipids accounted for less than 5% of the total cpm. HPLC analysis of the lipid mediators released during stimulation with 0.1 micrograms/ml anti-IgE revealed [3H]LTC4 (2.4 +/- 1.0%), [3H]5HETE (1.0 +/- 0.1%), unmetabolized [3H]AA (91 +/- 2%), and an unidentified peak (3.4 +/- 1.4%). The unknown metabolite eluted with the prostaglandins, was inhibited by indomethacin, and appeared to have a relatively high specific activity. It may thus represent an artifact of the labeling procedure rather than a novel basophil-derived prostaglandin.

Arachidonic Acids↗
PubMed1984

Structure and function of the anaphylatoxins.

Chemical and physical characterization of the anaphylatoxin molecules have provided a reasonably clear description of the architecture of these bioactive proteins. The primary structures of C3a, C4a, and C5a from man and from a number of animal species have been elucidated, and it is apparent that the three anaphylatoxins are genetically related. The anaphylatoxin protein chains very in length from 74 to 78 residues and no fewer than 30% of the residues are homologous when comparing C3a, C4a, and C5a within or between species. Synthetic peptide studies have been instrumental in identifying molecular features essential for the function of anaphylatoxins. Information gleaned from the structure-function studies with synthetic analogue peptides of the anaphylatoxins define putative "active sites" in these effector molecules. Linear sequences at the carboxy-terminus of C3a and C4a fulfill all of the criteria of an "active site," in that synthetic peptides of an identical sequence can mimic the biologic actions of the natural factors. In the case of human C3a, a crystallographic analysis has been performed and a three-dimensional structure was elucidated at the 3.2 A level. The crystalline structure of C3a provides valuable new information regarding the alpha helical regions and identifies the arrangement of intra-chain disulfide linkages. Taken together, the structural data now accumulated for anaphylatoxins permit molecular modelling of these proteins, designates favored conformational arrangements of the native structures, and specifically localizes the effector sites. Furthermore, elements at the essential active site have been defined with such precision that models are proposed detailing the exact nature of ligand interactions between anaphylatoxins and specific cellular receptors. Biologic characterization of the anaphylatoxins continues at a rapid pace and each advance provides a clearer view of the role of these humoral mediators in host defense. A variety of responses to anaphylatoxins are known to occur at the cellular level and are mediated in a hormone-like fashion. Diversity of action for these factors at the tissue level is readily explained by the numerous cell types stimulated by the anaphylatoxins. Cellular responses to the anaphylatoxins are perhaps the most easily defined and studied; however, tissue and systemic effects more accurately reflect the physiologic role of anaphylatoxins. Considerable progress has been made in understanding the mechanisms whereby anaphylatoxins mediate two major tissue effects, namely enhancement of vascular permeability and induction of smooth muscle contraction.(ABSTRACT TRUNCATED AT 400 WORDS)

Amino Acid Sequence↗
PubMed1987

Thrombin chemotactic stimulation of HL-60 cells: studies on thrombin responsiveness as a function of differentiation.

Thrombin, a major procoagulant enzyme and growth factor, is also selectively chemotactic for monocytes and macrophages but not for neutrophils. This effect stands in contrast to other well-known chemotactic agents such as fMet-Leu-Phe, C5a fragments, and LTB4, which stimulate directed cell movement in both cell types, and have important physiological implications. The human leukemic cell line HL-60, which is capable of differentiating either along granulocytic or monocytic lineages, was therefore used to explore the development of this selective monocyte/macrophage chemotactic response to thrombin. Esterolytically inactive DIP-alpha-thrombin, as well as the thrombin-derived chemotactic peptide CB67-129, elicits a dose-dependent chemotactic response in HL-60 cells differentiated to monocytelike cells by treatment with 1,25(OH)2D3 (HL-60/mono), whereas no such response is evident in either undifferentiated HL-60 cells or in cells differentiated into granulocytes by treatment with DMSO (HL-60/gran). Similarly, early events which characterize stimulation of inflammatory cells by chemotactic agents are also evident, but only in monocyte-differentiated cells. In HL-60/mono, thrombin selectively stimulates rapid cytosolic Ca2+ elevation as well as rapid cytoskeletal association of cytosolic actin. Following thrombin stimulation, maximal actin association in these cells occurs within 30 sec (declining to basal levels at the end of 5 min), and maximal Ca2+ elevations are also evident within 15-20 sec, suggesting a temporal relationship between these two events. Thus, the events accompanying stimulation of HL-60/mono by thrombin are characteristic of those seen following stimulation of inflammatory cells by chemotaxins, with a major difference being the selectivity of thrombin as a chemotaxin for cells of macrophage/monocytic lineage. The selective chemotactic responsiveness of HL-60/mono to thrombin appears to relate to the development of specific receptors on these cells as part of monocytic differentiation: HL-60/mono (but HL-60/gran nor undifferentiated HL-60) are capable of significant specific 125-I-labeled alpha-thrombin-binding (ka approximately 20 nM), and possess an estimated 400,000 thrombin-binding sites per cell. Our findings further suggest that the thrombin response of HL-60 and particularly the expression of thrombin receptors on these cells may serve as a useful model system for exploring the biology of monocyte/macrophage differentiation.

Actins↗
PubMed1990

Calcium mobilization in C5a-stimulated adult and newborn bovine neutrophils.

Calcium (Ca2+) is an important second messenger central to many neutrophil (PMN) functional activities. Impaired Ca2+ mobilization in newborn PMNs following membrane perturbation could be one of the mechanisms underlying observed abnormalities in neonatal PMN function. To compare Ca2+ mobilization in bovine newborn and adult PMNs, cytosolic Ca2+ responses after stimulation with recombinant human C5a (rHC5a) were measured. PMNs from normal newborn calves (N = 6) and adult cows (N = 5) were loaded with fura-2/AM for 60 min at room temperature and the fluorescence changes monitored following stimulation with 0.1, 1, 10, or 50 nM rHC5a in Ca2(+)-containing buffer. Resting levels of Ca2+ in both newborn (54.6 +/- 1.9 nM) and adult (57.3 +/- 1.8 nM) bovine PMNs were comparable. After stimulation with rHC5a, a rapid rise of cytosolic Ca2+ was observed, which peaked within 20 sec and was followed by a sustained phase of elevated Ca2+ lasting up to 20 min. There were no significant differences (P greater than 0.05) in peak levels of cytosolic Ca2+ obtained by newborn and adult PMNs at 0.1, 10, and 50 nM rHC5a. At 1 nM rHC5a, newborn PMNs reached significantly (P less than 0.05) higher levels of cytosolic Ca2+ (217.9 +/- 21.7 nM) than did adult PMNs (158.7 +/- 7.9 nM). At 1 nM rHC5a, newborn PMNs also sustained higher levels of cytosolic Ca2+ for 3 min following the peak. At all concentrations of rHC5a tested, the time required to reach the peak and the duration of the peak were comparable in both populations. In the absence of extracellular Ca2+ (Ca2(+)-free buffer with 1 mM EGTA), resting levels of cytosolic Ca2+ were lower in both newborn (33.3 +/- 2.9 nM) and adult PMNs (27.9 +/- 2.4 nM) and the magnitude of the peak response to rHC5a was diminished at all concentrations of agonist. Additionally, in the absence of extracellular Ca2+, the return to basal cytosolic Ca2+ levels occurred rapidly and the sustained phase of increased cytosolic Ca2+ seen with rHC5a-stimulated PMNs in Ca2(+)-containing buffer was virtually eliminated. These results indicate that bovine PMNs respond well to rHC5a, that stimulated newborn bovine PMNs can mobilize Ca2+ as efficiently as adult PMNs, and that the sustained cytosolic Ca2+ response to rHC5a in both age groups requires both release of Ca2+ from intracellular stores as well as influx of extracellular Ca2+. Such data suggest that observed functional deficits in newborn bovine PMNs are probably not related to improper mobilization of Ca2+ following stimulation.

Aging↗
PubMed1995

Chemoattractants induce rapid release of the interleukin 1 type II decoy receptor in human polymorphonuclear cells.

Molecules representative of different classes of chemotactic agents, including formyl-Met-Leu-Phe (FMLP), C5a, leukotriene B4, platelet-activating factor, and interleukin (IL)-8, caused a rapid reduction in the IL-1 binding capacity by human polymorphonuclear leukocytes (PMN), a cell type expressing predominantly the IL-1 type II decoy receptor (IL-1 decoy RII). N-t-Boc-Met-Leu-Phe, an antagonist for the FMLP receptor, inhibited the loss of IL-1 binding capacity induced by FMLP. Monocyte chemotactic protein 1, a chemokine related to IL-8 but inactive on PMN, had no effect on IL-1 binding in this cell type. FMLP was selected for further detailed analysis of chemoattractant-induced loss of IL-1 binding by PMN. The action of FMLP was rapid, reaching 50% of its maximum (80%) at 30 s, the earliest measurable time point, and plateauing between 10 and 30 min. Dose-response analysis revealed that maximal reduction of IL-1 binding was reached at FMLP concentrations that were also optimal for chemotaxis (50% effective dose = 5 x 10(-9) M). The loss of IL-1 binding capacity caused by FMLP was determined by a reduction in receptor number with no change in their affinity. The effect of FMLP on IL-1 receptor (IL-1R) was selective in that the PMN surface structures IL-8R, CD16, CD18, and major histocompatibility complex class I antigens were unaffected under these conditions. Loss of surface IL-1R was not due to an augumented rate of internalization. FMLP caused rapid release of a 45-kD IL-1-binding molecule identified as the IL-1 decoy RII. After FMLP-induced release, PMN reexpressed newly synthesized receptors, reaching basal levels by 4 h. FMLP-induced release of the IL-1 decoy RII did not impair the responsiveness of PMN to IL-1 in terms of promotion of survival and cytokine production. FMLP-induced release of the IL-1 decoy RII was unaffected by protein synthesis inhibitors, was blocked by certain protease inhibitors, and was mimicked by agents (the Ca++ ionophore A23187 and phorbol myristate acetate) that recapitulate elements in the signal transduction pathway of chemoattractant receptors. The time frame and concentration range of chemoattractant-induced rapid release of the IL-1 decoy RII are consistent with the view that IL-1 decoy RII release is an early event in the multistep process of leukocyte recruitment.(ABSTRACT TRUNCATED AT 400 WORDS)

Amino Acid Sequence↗
PubMed1999

Chemokine regulation of neutrophil function in surgical inflammation.

BACKGROUND: Morbidity and even mortality correlate closely with major injury that causes a systemic inflammatory response. Cytokines and bioactive molecules present at the inflammatory site induce this response and regulate neutrophil proinflammatory responses. The CXC chemokines, important for neutrophil recruitment and activation, include interleukin 8 (IL-8), granulocyte chemotactic protein 2 (GCP-2), and epithelial cell-derived neutrophil attractant 78 (ENA-78). They induce neutrophil responses via 2 cell-surface receptors, CXCR-1 and CXCR-2. All 3 chemokines bind CXCR-2 with high affinity. Only IL-8 and GCP-2 bind CXCR-1 with high affinity. HYPOTHESIS: The CXC chemokines regulate neutrophil responses differently. METHODS: Pretreatment of neutrophils from healthy volunteers with IL-8, GCP-2, or ENA-78; measured IL-8-induced migration; and tumor necrosis factor alpha (TNF-alpha)-induced peroxide production. RESULTS: Flow cytometry and radioligand binding data indicate that IL-8, GCP-2, and ENA-78 equivalently reduced CXCR-1 and CXCR-2 cell surface expression by 34% to 54%. All treatments decreased affinity of both receptors 1.5- to 2-fold. However, only IL-8 pretreatment inhibited chemotaxis to 10-nmol/L IL-8 (mean +/- SE inhibition, 62%+/-6%). Although IL-8 and GCP-2, but not ENA-78, suppressed TNF-alpha-induced oxidant production (mean +/- SE inhibition, 42%+/-8% and 40%+/-23%, respectively), only GCP-2 inhibited the oxidative response to complement fragment C5a, and to the bacterial cell wall peptide N-formyl-methionyl-leucyl-phenylalanine. CONCLUSIONS: The CXC chemokines regulate neutrophil proinflammatory functions differently. A thorough understanding of mechanisms for modulating neutrophil responses in inflammation will aid the development of interventions that reduce morbidity and mortality associated with severe trauma and sepsis.

Chemokine CXCL5↗
PubMed1986

Trauma serum suppresses superoxide production by normal neutrophils.

The effect of trauma serum on superoxide production by normal neutrophils was studied in 47 serum samples from 18 patients with multiple trauma. Ten patients became septic and eight patients remained nonseptic. Incubation in trauma serum significantly suppressed superoxide production by normal neutrophils compared with incubation in normal serum: 3.6 +/- 1.44 vs 4.04 +/- 1.64 nmole of superoxide produced by 10(6) neutrophils (mean +/- SD). There was no difference in the suppressive effect between septic and nonseptic trauma serum samples. The chemiluminescence response of normal neutrophils was likewise suppressed following incubation in trauma serum compared with incubation in normal serum. The chemiluminescence response correlated with superoxide reduction of cytochrome C. In addition, the chemiluminescence response was significantly less in septic-trauma serum than in nonseptic-trauma serum. Suppressive serum was found to inhibit the neutrophil-membrane depolarization response to latex particles, as measured by flow cytometry. We conclude that trauma serum suppresses superoxide production by normal neutrophils, and that such suppression can be detected reliably using the clinically applicable technique of chemiluminescence. A normal chemiluminescence response excludes serum-mediated suppression of neutrophil superoxide production. In addition, chemiluminescence may be of value in detecting altered resistance to sepsis following injury, while superoxide determinations do not seem to be helpful in this regard. The mechanism of action of the suppressor may involve reversible inhibition of membrane depolarization necessary for the production of bactericidal oxygen species.

Adolescent↗
PubMed1987

Complement-mediated neutrophil activation in sepsis- and trauma-related adult respiratory distress syndrome. Clarification with radioaerosol lung scans.

Complement-mediated neutrophil activation (CMNA) has been proposed as an important pathogenic mechanism causing acute microvascular lung injury in the adult respiratory distress syndrome (ARDS). To clarify the relationship between CMNA and evolving lung injury, we studied 26 patients with multiple trauma and sepsis within 24 hours of risk establishment for ARDS. Pulmonary alveolar-capillary permeability (PACP) was quantified as the clearance rate of a particulate radioaerosol. Seventeen patients (65%) had increased PACP (six developed ARDS) while nine (35%) had normal PACP (none developed ARDS; clearance rates of 3.4%/min and 1.5%/min, respectively). These patients, regardless of evidence of early lung injury, had elevated plasma C3adesArg levels and neutrophil chemotactic desensitization to C5a/C5adesArg. Plasma C3adesArg levels correlated weakly, but significantly, with PACP. Thus, CMNA may be a necessary, but not a sufficient, pathogenic mechanism in the evolution of ARDS.

Adult↗
PubMed1990

Anaphylatoxins and terminal complement complexes in pancreatitis. Evidence of complement activation in plasma and ascites fluid of patients with acute pancreatitis.

Complement activation has been proposed as a mediator of remote complications of acute pancreatitis. Thirty-seven patients with acute pancreatitis were studied with respect to the formation of anaphylatoxins (C3a/C3adesArg, C5a/C5adesArg) and terminal complement complexes (TCC) in plasma and ascites fluid. The patients were classified according to Ranson's criteria. Eighteen patients with moderate or severe pancreatitis had higher maximum plasma C3a/C3adesArg and TCC concentrations than 19 patients with mild pancreatitis. During convalescence, the concentrations had returned to normal. High concentrations of C5a/C5adesArg and TCC were also found in ascites and pancreatic cyst fluid, drawn from patients with moderate or severe pancreatitis. As the terminal complement pathway activation is involved in reactive lysis and anaphylatoxins increase vascular permeability, anemia and impaired respiration in these patients may be influenced by complement activation.

Acute Disease↗
PubMed1990

Responses of neutrophils to myeloid growth factors.

Colony-stimulating factors (CSFs) have important effects on mature myeloid cells in addition to their regulatory role in haemopoiesis. Exposure of neutrophils to granulocyte macrophage-CSF (GM-CSF) increases chemotaxis, phagocytosis and cytotoxicity and primes the cells for enhanced oxidative metabolism in response to stimuli, such as formylated oligopeptides derived from bacteria (f-Met-Leu-Phe) and endogenous activated complement components (C5a). GM-CSF induces time-dependent changes in neutrophil f-Met-Leu-Phe receptor number and affinity that correspond to changes in functional activity. The neutrophil IgA Fc receptor is also modulated by GM-CSF such that it develops a high affinity state and transduces a phagocytic signal. The ability to regulate the number and activity of mature myeloid effector cells in vivo establishes unique therapeutic opportunities in the area of infectious disease, cancer treatment, bone marrow transplantation and augmentation of host defence in immunodeficient patients.

Animals↗
PubMed1984

Migration of porcine endothelial and smooth muscle cells in response to platelet-associated factors.

A NeuroProbe multiwell microchemotaxis assembly has been used to study the migration of porcine aortic endothelial and smooth muscle cells in vitro in response to serum factors. Whole pig serum was found to be chemokinetic for endothelial cells but not smooth muscle cells. Chemokinetic activity was higher in platelet-enriched, plasma-derived serum (PDS) than in platelet-free PDS. The supernatant from washed, lysed pig platelets also showed chemokinetic activity both for endothelial and smooth muscle cells. Chromatography on Sephadex G-200 showed that the lysate contained a number of activities that act independently on the two cell types. The chemokinetic activity that we have detected appears to be distinct from the chemotactic effect of platelet-derived growth factor and platelet factor 4 on the basis of insensitivity to protamine sulfate and molecular size. The role of these platelet factors in pathological changes in vascular structure is currently under study.

Animals↗
PubMed1993

Neutrophil attractant/activation protein-1 (interleukin-8) induces in vitro neutrophil migration by haptotactic mechanism.

The role of leukocyte migration induced by the substrate-bound attractants is obscured by the inability of standard methods for the study of leukocyte migration to dissociate chemotaxis and haptotaxis, migration in response to soluble and surface-bound gradients of attractants. Here we show that the gradient of neutrophil attractant/activation protein-1 (interleukin-8, NAP-1/IL-8) induces directed in vitro neutrophil migration when bound to the polycarbonate filter. In addition, we suggest that haptotaxis is responsible for neutrophil migration induced by NAP-1/IL-8 in standard Boyden-type chemotaxis assays and, in light of the ability of NAP-1/IL-8 to bind to the endothelial cell surface and the extracellular matrix, could also be of great significance in vivo.

Chemotaxis, Leukocyte↗
PubMedDate not supplied

Activation of liver macrophages following phenobarbital treatment of rats.

Phenobarbital is a potent inducer of hepatic cytochrome P-450 and is a tumor promoter in the two-stage model of liver carcinogenesis. In the present studies, we show that phenobarbital also induces an accumulation of activated macrophages in the livers of treated rats. These macrophages are larger and more stellate than resident Kupffer cells and are highly vacuolated. In addition, macrophages isolated from livers of phenobarbital-treated rats display increased phagocytosis of sheep red blood cells, chemotaxis toward the complement fragment C5a and enhanced production of hydrogen peroxide. Biologically active mediators released by activated macrophages have been implicated in tumor promotion as well as in the regulation of cytochrome P-450-mediated drug biotransformation. We propose that the activated macrophages that accumulate in the liver following phenobarbital treatment may contribute, at least in part, to the biological responses to this drug.

Animals↗