PubMed Health⌕ Search

Biomedical subjects

C Rosales

Publications and source records attributed to C Rosales.

At least 19 recordsLinked to original sources
PubMed2001

Investigation of systemic lupus erythematosus in Nogales, Arizona.

In 1996, a citizens group in Nogales, Arizona, reported to the Arizona Department of Health their concerns about a possible excess prevalence of systemic lupus erythematosus (SLE) due to exposure to environmental contamination in the area. The authors conducted a two-phase study in which the objectives of phase I were to identify potential SLE cases and to determine the prevalence of SLE and the objectives of phase II were to identify potential risk factors associated with the development of SLE and to evaluate the possible association between SLE and environmental exposure to pesticides and inorganic compounds. Participants included 20 confirmed cases and 36 controls. The authors found the prevalence of SLE to be 103 cases per 100,000 population (95 percent confidence interval: 56, 149), two to seven times higher than the prevalence in the US population. They detected elevated levels of 1,1-dichloro-2,2-bis-(p-chorophenyl)ethylene and organophosphate metabolites among cases and controls. In both, levels were higher than the reference mean for the US population. The authors found no statistical association between elevated levels of pesticides and disease status. Their results show that the prevalence of SLE in Nogales is higher than the reported prevalence in the US population and that both cases and controls had past exposure to chlorinated pesticides and have ongoing exposure to organophosphates.

Arizona↗
PubMed2001

Phosphatidylinositol 3-kinase mediates integrin-dependent NF-kappaB and MAPK activation through separate signaling pathways.

Integrin-mediated signals play an important but poorly understood role in regulating many leukocyte functions. In monocytes and monocytic leukemia cells, beta1 integrin-mediated adhesion results in a strong induction of immediate-early genes that are important in inflammation. To investigate the signaling pathways from integrins in monocytic cells, THP-1 cells were stimulated via beta1 integrins by binding to fibronectin and by crosslinking the integrins with specific monoclonal antibodies. The involvement of MAPK and PI 3-K on nuclear factor kappaB (NF-kappaB) activation was then analyzed. We found that integrins activated both NF-kappaB and MAPK in a PI 3-K-dependent manner, as wortmannin and LY294002 blocked these responses. However, the specific MEK inhibitor PD98059 did not prevent integrin-mediated NF-kappaB activation. In contrast, a dominant negative mutant of Rac completely prevented NF-kappaB activation, but it did not affect MAPK activation. These results indicate that integrin signaling to NF-kappaB is not mediated by the MAPK pathway, but rather by the small GTPase Rac. In addition, a dominant negative form of Rho augmented NF-kappaB activation and blocked MAPK activation, implying that these two pathways are in competition with each other. These data suggest that integrins activate different signaling pathways in monocytic cells. One uses PI 3-K and Rac to activate NF-kappaB, while the other uses PI 3-K, MEK, and MAPK to activate other nuclear factors, such as Elk-1.

Cytoskeleton↗
PubMed2001

What's being used at home: a household pesticide survey.

OBJECTIVE: Since very little is known about the health effects that household pesticides have on children, we conducted this survey to identify what pesticides are being used in the home, where they are being used and stored, and what methods are used for their disposal. METHODS: In the spring of 1999 we conducted a survey in a community in the state of Arizona, in the United States of America, on the border with Mexico. To be eligible to participate in the survey, households had to have used a pesticide in the 6 mo prior to the survey and to have at least one child under the age of 10 years. We gathered general information on pesticide usage, storage, and disposal, in addition to specific information about each of the pesticides currently being used and/or stored in the home. RESULTS: In the 107 households surveyed, we found 148 pesticide products, for a mean of 1.4 per household. Half of the pesticides were stored less than 4 feet (1.22 m) from the ground, at a level a child could reach. Seventy percent of all the pesticides were stored inside the home, with the kitchen being the storage room most often mentioned. The kitchen was also the room where most of the pesticides were used, with 69% of the respondents saying they had used at least one pesticide there. CONCLUSIONS: From our research we conclude that it will be important to continue to investigate all avenues of pesticide exposure in order to fully evaluate childhood exposures. Understanding household pesticide use and developing a model of exposure will help in this process. Profiles of the use, storage, and disposal of products will also guide the development of effective education and poison prevention programs in the community.

Child↗
PubMed2001

Comorbidity of axis I disorders in patients with traumatic grief.

BACKGROUND: Traumatic grief has been found to be a distinct disorder from both depression and anxiety; however, there is no information in the literature regarding comorbidity of traumatic grief with other psychiatric disorders. METHOD: Twenty-three bereaved subjects who presented for treatment of traumatic grief symptomatology were included in this study. The Inventory of Complicated Grief (ICG) was used to confirm the presence of traumatic grief and assess its severity. In addition, the Structured Clinical Interview for DSM-IV was performed. RESULTS: Most subjects met criteria for a current or lifetime Axis I diagnosis. Fifty-two percent (N = 12) met criteria for current major depressive disorder, and 30% (N = 7), for current posttraumatic stress disorder (PTSD). ICG scores and functional impairment were higher among patients with more than one concurrent Axis I diagnosis. CONCLUSION: Comorbid major depressive disorder and PTSD may be prevalent in patients presenting for treatment of traumatic grief.

Adult↗
PubMed2001

Phosphatidylinositol 3-kinase and ERK are required for NF-kappaB activation but not for phagocytosis.

The molecular events that transduce signals from Fc receptors to the various cellular responses are still poorly defined. We have investigated the role of phosphatidylinositol 3-kinase (PI 3-K) and extracellular signal-regulated kinase (ERK) in gene activation and phagocytosis in monocytes. In the THP-1 monocytic cell line, cross-linking of Fc receptors by immune complexes results in activation of the transcription factor NF-kappaB, via activation of ERK. Activation of both ERK and NF-kappaB was blocked by wortmannin and LY294002, specific inhibitors of PI 3-K. Wortmannin also inhibited the Fc receptor-mediated increase in the cytosolic calcium concentration, but it did not block immunoglobulin G (IgG)-mediated phagocytosis. In addition, the ERK inhibitor PD98059 did not block phagocytosis of IgG-coated erythrocytes. Both the increase in the cytosolic calcium concentration and phagocytosis depend on an active actin cytoskeleton, as indicated by the total lack of both responses after treatment with cytochalasin B. In contrast, cytochalasin B did not affect Fc receptor-mediated activation of NF-kappaB. These results identify PI 3-K and ERK as important signaling molecules in the Fc receptor signal transduction pathway of monocytes, which leads to the nucleus for gene activation. These results also suggest that, in contrast to other cell types, unstimulated monocytes do not require PI 3-K and ERK for phagocytosis.

Actin Cytoskeleton↗
PubMed2000

A recombinant vaccinia virus containing the papilloma E2 protein promotes tumor regression by stimulating macrophage antibody-dependent cytotoxicity.

Human papillomavirus infection is associated with cervical cancer. The E6 and E7 papillomavirus proteins are normally required for the maintenance of the malignant phenotype. Expression of these proteins in infected cells is negatively regulated by the binding of the papilloma E2 protein to the long terminal control region of the papilloma virus genome. The E2 protein can also promote cell arrest and apoptosis in HeLa cells. Therefore, it is clear that this protein has the potential of inhibiting the malignant phenotype. Because, anticancer vaccines based in vaccinia viruses have recently been shown to be an effective way to treat and to eradicate tumors, a recombinant vaccinia virus expressing the E2 gene of bovine papilloma virus (Modified Vaccinia Ankara, MVA E2) was created, to explore further the antitumor potential of the E2 protein. A series of rabbits, containing the VX2 transplantable papilloma carcinoma, were treated with MVA E2. An impressive tumor regression, up to a complete disappearance of tumor, was observed in most animals (80%). In contrast, very little or no regression was detected if the normal vaccinia virus was used. Lymphocytes isolated from MVA E2-treated rabbits did not show cytotoxic activity against tumor cells. However, in these animals a humoral immune response against tumor cells was observed. These antitumor antibodies were capable of activating macrophages to destroy tumor cells efficiently. These data indicate that injecting the MVA E2 recombinant vaccinia virus directly into the tumor results in a robust and long-lasting tumor regression. Data also suggest that antitumor antibodies are responsible, at least in part, for eliminating tumors by activating macrophage antibody-dependent cytotoxicity.

Amino Acid Sequence↗
PubMed2000

Butyrate inhibits inflammatory responses through NFkappaB inhibition: implications for Crohn's disease.

BACKGROUND/AIM: Proinflammatory cytokines are key factors in the pathogenesis of Crohn's disease (CD). Activation of nuclear factor kappa B (NFkappaB), which is involved in their gene transcription, is increased in the intestinal mucosa of CD patients. As butyrate enemas may be beneficial in treating colonic inflammation, we investigated if butyrate promotes this effect by acting on proinflammatory cytokine expression. METHODS: Intestinal biopsy specimens, isolated lamina propria cells (LPMC), and peripheral blood mononuclear cells (PBMC) were cultured with or without butyrate for assessment of secretion of tumour necrosis factor (TNF) and mRNA levels. NFkappaB p65 activation was determined by immunofluorescence and gene reporter experiments. Levels of NFkappaB inhibitory protein (IkappaBalpha) were analysed by western blotting. The in vivo efficacy of butyrate was assessed in rats with trinitrobenzene sulphonic acid (TNBS) induced colitis. RESULTS: Butyrate decreased TNF production and proinflammatory cytokine mRNA expression by intestinal biopsies and LPMC from CD patients. Butyrate abolished lipopolysaccharide (LPS) induced expression of cytokines by PBMC and transmigration of NFkappaB from the cytoplasm to the nucleus. LPS induced NFkappaB transcriptional activity was decreased by butyrate while IkappaBalpha levels were stable. Butyrate treatment also improved TNBS induced colitis. CONCLUSIONS: Butyrate decreases proinflammatory cytokine expression via inhibition of NFkappaB activation and IkappaBalpha degradation. These anti-inflammatory properties provide a rationale for assessing butyrate in the treatment of CD.

Adolescent↗
PubMed1998

Fcgamma receptor-mediated mitogen-activated protein kinase activation in monocytes is independent of Ras.

Receptors for the Fc portion of immunoglobulin molecules (FcR) present on leukocyte cell membranes mediate a large number of cellular responses that are very important in host defense, including phagocytosis, cell cytotoxicity, production and secretion of inflammatory mediators, and modulation of the immune response. Cross-linking of FcR with immune complexes leads, first to activation of protein-tyrosine kinases. The molecular events that follow and that transduce signals from these receptors to the nucleus are still poorly defined. We have investigated the signal transduction pathway from Fc receptors that leads to gene activation and production of cytokines in monocytes. Cross-linking of FcR, on the THP-1 monocytic cell line, by immune complexes resulted in both activation of the transcription factor NF-kappaB and interleukin 1 production. These responses were completely blocked by tyrosine kinase inhibitors. In contrast, expression of dominant negative mutants of Ras and Raf-1, in these cells, did not have any effect on FcR-mediated nuclear factor activation, suggesting that the mitogen-activated protein kinase (MAPK) signaling pathway was not used by these receptors. However, MAPK activation was easily detected by in vitro kinase assays, after FcR cross-linking with immune complexes. Using the specific MAPK/extracellular signal-regulated kinase kinase (MAPK kinase) inhibitor PD98059, we found that MAPK activation is necessary for FcR-dependent activation of the nuclear factor NF-kappaB. These results strongly suggest that the signaling pathway from Fc receptors leading to expression of different genes important to leukocyte biology, initiates with tyrosine kinases and requires MAPK activation; but in contrast to other tyrosine kinase receptors, FcR-mediated MAPK activation does not involve Ras and Raf.

Antigen-Antibody Complex↗
PubMed1998

Signal transduction by immunoglobulin Fc receptors.

Receptors for the Fc portion of immunoglobulin molecules (FcR) present on leukocyte cell membranes mediate a large number of cellular responses that are very important in host defense. Cross-linking of FcR by immune complexes leads to functions such as phagocytosis, cell cytotoxicity, production and secretion of inflammatory mediators, and modulation of the immune response. Molecular characterization of FcRs indicates the existence of several types of these receptors, which seem to be redundant in their cell distribution and function. There is a great deal of interest in understanding how these various receptors signal the cell to respond in different ways during inflammation and the immune response. Previous studies indicate that FcR signaling shares elements with the T and B cell antigen receptors. Signaling is initiated in all of them by activation of tyrosine kinases of the Src and ZAP-70 families. Subsequent events, which vary depending on the cell type and receptor involved, include activation of other enzymes such as phospholipase Cgamma1, phosphatidylinositol-3-kinase, and mitogen-activated protein kinase. Several recent lines of research, including studies of phagocytosis by FcR-transfected cells, antibody-dependent cytotoxicity by natural killer cells, mast cell degranulation, and FcR-deficient mice, have given us new insights on the signal transduction pathways activated by FcRs. This review describes the advances in these areas and presents a general model for FcR-mediated signaling.

Animals↗
PubMed1998

Anoxia during kainate status epilepticus shortens behavioral convulsions but generates hippocampal neuron loss and supragranular mossy fiber sprouting.

In rats, this study determined the impact of systemic hypoxia during late kainate-induced status epilepticus on hippocampal neuron loss and mossy fiber sprouting. Non-fasted Sprague Dawley rats were prepared as follows: Naive controls (n=5); rats placed 2 min in a hypoxia chamber (hypoxia only; n=6); rats that seized for more than 6 h from kainic acid (KA-status; 12 mg/kg; i.p.; n=7); and another KA-status group placed into the hypoxia chamber 75 min after the convulsions started (KA-status/hypoxia; n=16). All rats, except for half of the KA-status/hypoxia animals, were perfused 2 weeks later (short-term). The other 8 KA-status/hypoxia rats were perfused after 2 months (long-term). Hippocampal sections were studied for neuron densities and aberrant mossy fiber sprouting at three ventral to dorsal levels. Fascia dentata (FD) mossy fiber sprouting was quantified as an increase in the inner minus outer molecular layer (IML-OML) gray value (GV) difference. Behaviorally, KA-status/hypoxia rats had a shorter duration of convulsive status epilepticus than KA-status animals without anoxia. Hippocampal sections showed that compared to controls: (1) hypoxia-only rats showed no differences in ventral neuron densities and neo-Timm's stained IML-OML GVs; (2) KA-status rats had decreased CA3 densities and a non-significant increase in ventral IML-OML GV differences; and (3) KA-status/hypoxia short-term animals showed decreased hilar, CA3 and CA1 densities and increased ventral IML-OML GV differences. Compared to KA-status/hypoxia short-term rats, long-term animals showed no differences in ventral hippocampal neuron densities, but middle and dorsal sections demonstrated increased IML-OML GV differences and animals were observed to have spontaneous limbic epilepsy. These results indicate that rats exposed to kainate-induced status epilepticus for over 1 h and then a hypoxic insult had a shorter duration of convulsive status, decreased hippocampal neuron densities and greater FD mossy fiber sprouting than controls and the amount of neuronal damage and sprouting was slightly more than animals subjected to 6 h of kainate-induced status. This supports the hypothesis that a physiologic insult during status can shorten the convulsive episode, but still produce hippocampal pathology with a number of clinical and pathologic similarities to human mesial temporal lobe epilepsy (MTLE).

Animals↗
PubMed1996

Integrin signaling to NF-kappa B in monocytic leukemia cells is blocked by activated oncogenes.

Integrin-mediated signals play an important but poorly understood role in regulating the growth and behavior of tumor cells. In monocytes and monocytic leukemia cells, integrin-mediated adhesion results in a strong induction of a set of immediate early genes that are characteristic of monocytic differentiation and contain consensus NF-kappa B elements in their 5' regulatory regions. To investigate the role of integrin signaling in control of differentiation in a human monocytic leukemia cell line, THP-1 cells were transiently transfected with an NF-kappa B driven CAT reporter gene. Adhesion to fibronectin or cross-linking of beta1 integrins resulted in an NF-kappa B-dependent induction of CAT activity. To evaluate whether integrin signaling in this system intersects with the Ras signal transduction cascade, THP-1 cells were cotransfected with the NF-kappa B reporter and with plasmids that direct the synthesis of normal or mutant forms of Ras or Raf. We found that Ras or Raf dominant negative mutants did not inhibit integrin-mediated activation of the NF-kappa B-driven reporter. However, cotransfection with activated Ras, or with several other cytoplasmic oncogenes, blocked this process. This suggests that in monocytic leukemia cells, an antagonism exists between the mitogenic signals provided by oncogenes and the signals generated by integrin ligation. This antagonism may play an important role in regulating the balance between proliferation and differentiation in monocytic leukemias.

Cell Adhesion↗
PubMed1995

Signal transduction by cell adhesion receptors.

Over the last few years, it has become clear that cell adhesion receptors function in signal transduction processes leading to the regulation of cell growth and differentiation. Signal transduction by both integrins and CAMs has been shown to involve activation of tyrosine kinases, while CAM signaling in neural cells involves G proteins as well. In the case of integrins, some of the downstream signaling events intersect with the Ras pathway, particularly the activation of MAP kinases. In fibroblasts, integrin mediated anchorage to the substratum regulates cell cycle traverse, while in epithelial cells, loss of anchorage can trigger programmed cell death. In many cell types, but particularly monocytic cells, integrin ligation has a profound impact on gene expression. Preliminary evidence also implicates CAMs and selectins in gene regulation. A consistent theme in signal transduction mediated by adhesion receptors concerns the role of the cytoskeleton. Integrin mediated signaling processes are interrupted by cytoskeletal disassembly. Identification of the APC and neurofibromatosis type 2 tumor suppressors suggest that cytoskeletal complexes also play a key role in signaling by cadherins and CD44, respectively. Thus, signaling by cell adhesion receptors may involve aspects that impinge on previously known signaling pathways including the RTK/Ras pathway and serpentine receptor/G protein pathways. However, novel aspects of signal transduction involving cytoskeletal assemblies may also be critical.

Animals↗
PubMed1995

Integrin-mediated tyrosine phosphorylation and cytokine message induction in monocytic cells. A possible signaling role for the Syk tyrosine kinase.

Activation of cytoplasmic tyrosine kinases is an important aspect of signal transduction mediated by integrins. In the human monocytic cell line THP-1, either integrin-dependent cell adhesion to fibronectin or ligation of beta 1 integrins with antibodies causes a rapid and intense tyrosine phosphorylation of two sets of proteins of about 65-75 and 120-125 kDa. In addition, integrin ligation leads to nuclear translocation of the p50 and p65 subunits of the NF-kappa B transcription factor, to activation of a reporter gene driven by a promoter containing NF-kappa B sites, and to increased levels of mRNAs for immediate-early genes, including the cytokine interleukin (IL)-1 beta. The tyrosine kinase inhibitors genistein and herbimycin A block both integrin-mediated tyrosine phosphorylation and increases in IL-1 beta message levels, indicating a causal relationship between the two events. The components tyrosine phosphorylated subsequent to cell adhesion include paxillin, pp125FAK, and the SH2 domain containing tyrosine kinase Syk. In contrast, integrin ligation with antibodies induces tyrosine phosphorylation of Syk but not of FAK or paxillin. In adhering cells, pre-treatment with cytochalasin D suppresses tyrosine phosphorylation of FAK and paxillin but not of Syk, while IL-1 beta message induction is unaffected. These observations indicate that the Syk tyrosine kinase may be an important component of an integrin signaling pathway in monocytic cells, leading to activation of NF-kappa B and to increased levels of cytokine messages.

Benzoquinones↗
PubMed1995

Signal transduction by cell adhesion receptors in leukocytes.

Leukocytes usually pass through the blood stream as nonadherent cells, but during an immune response and inflammation, they become adherent in order to migrate through tissues. Three families of adhesion molecules, the immunoglobulin family, the selectins, and the integrins, participate in interactions between leukocytes and tissues. Near sites of inflammation, leukocytes initially interact with the endothelium via selectins, causing them to slow down and to roll along the walls of blood vessels. Next, chemoattractans induce the activation of integrins on leukocytes. Finally, activated integrins mediate leukocyte migration through the endothelium into the inflamed site. Interactions of leukocytes with other cells and various extracellular matrix (ECM) proteins lead to different functional cell responses, including changes in growth, behavior, and differentiation. Many of these interactions are mediated by integrins, which "integrate" ECM protein signals with the cytoskeleton and which also act as true receptors that generate biochemical signals within the cell. Changes in pH, cytoplasmic Ca2+ concentration, phosphorylation, and gene induction have all been observed after integrin engagement. Adhesion-mediated gene induction in monocytes is perhaps the best example that integrins initiate signaling cascades in the cell to deliver information from the ECM all the way to the nucleus.

Cell Adhesion↗
PubMed1994

Bromophenacyl bromide binding to the actin-bundling protein l-plastin inhibits inositol trisphosphate-independent increase in Ca2+ in human neutrophils.

Ligation of IgG Fc receptors on polymorphonuclear leukocytes causes an increase in the concentration of free intracytoplasmic Ca2+ ([Ca2+]i) which arises from release of intracellular stores but is independent of inositol 1,4,5-trisphosphate. We found that bromophenacyl bromide (BPB), an alkylating agent which inhibits leukocyte degranulation, adherence, and phagocytosis, inhibited IgG-stimulated increases in [Ca2+]i with an IC50 of 0.2 microM. In contrast, BPB had no effect on inositol 1,4,5-trisphosphate-dependent [Ca2+]i increases induced by fMet-Leu-Phe, complement fragment C5a, ATP, or platelet-activating factor. Using a monoclonal antibody specific for BPB, we identified in polymorphonuclear leukocytes a single cytosolic protein of 66 kDa and isoelectric point pH 5.6 which bound BPB when intact cells were treated with the alkylating agent. This BPB-binding protein was identified as l-plastin, a Ca(2+)-regulated actin-bundling protein. l-Plastin was found associated with the Triton X-100-insoluble cytoskeleton in polymorphonuclear leukocytes adherent to immune complexes, suggesting that BPB affects Fc receptor-mediated signal transduction by altering the actin cytoskeleton. Consistent with this hypothesis, both cytochalasin B and cytochalasin D inhibited the IgG-dependent increase in [Ca2+]i, without any effect on fMet-Leu-Phe-induced Ca2+ release. These data suggest that the actin cytoskeleton is essential for signal transduction from plasma membrane Fc receptors and that l-plastin has a critical role in activation of this pathway.

Acetophenones↗
PubMed1992

Expression of the 50-kDa integrin-associated protein on myeloid cells and erythrocytes.

Integrin-associated protein (IAP) is a 50-kDa intrinsic membrane protein that is involved in signal transduction during neutrophil activation by a variety of Arg-Gly-Asp-containing ligands. However, IAP does not itself directly bind these ligands, which are instead recognized by the leukocyte response integrin (LRI). In fact, IAP is more widely expressed than the LRI and is even on erythrocytes, which express no known integrins. This suggests that IAP may have additional functions besides signal transduction in association with the LRI. In this work we have quantitated IAP expression on several myeloid cells and cell lines, as well as erythrocytes, using a mAb which recognizes this protein. These data show that there are about 10,000 IgG-binding sites on each erythrocyte and 20 times that number on the myeloid cell lines U937 and HL60. Normal PMN and monocytes express about 25,000 IgG-binding sites. There are twice as many Fab'-binding sites on each cell, suggesting that each IgG binds via both Ag-combining sites. Binding data using several mAb to IAP suggest that IAP undergoes a temperature-dependent conformational change. Unlike some integrin receptors, IAP is not stored in a regulated secretory compartment in polymorphonuclear leukocytes (PMN). In addition, there is no evidence for internalization or shedding of IAP upon PMN activation. These data show that IAP is expressed at significant levels on myeloid cells and erythrocytes and that its expression is unaffected by the state of PMN activation.

Amino Acid Sequence↗
PubMed1992

Signal transduction by neutrophil immunoglobulin G Fc receptors. Dissociation of intracytoplasmic calcium concentration rise from inositol 1,4,5-trisphosphate.

The signal transduction mechanisms involved in the regulation of phagocytosis are largely unknown. We have recently shown that in neutrophils, when IgG-mediated phagocytosis is stimulated by formyl-methionyl-leucyl-phenyl-alanine (fMLP), the enhanced ingestion is dependent on the increase in [Ca2+]i which results from ligation of Fc receptors by the IgG-coated target (Rosales, C., and Brown, E. (1991) J. Immunol. 146, 3937-3944). Now, we have studied the mechanism by which this rise in [Ca2+]i occurs. Aggregated IgG, the monoclonal antibody 3G8 (which recognizes Fc receptor type III), and insoluble immune complexes caused an increase in [Ca2+]i. The rise in [Ca2+]i induced by Fc receptor ligation was resistant to pertussis toxin. In contrast, fMLP induced a rise in [Ca2+]i which was inhibited by pertussis toxin. fMLP-induced [Ca2+]i was accompanied by an accumulation of inositol 1,4,5-trisphosphate (IP3) which peaked by 15 s, and which was also abolished by pertussis toxin. IP3 accumulation after aggregated IgG, 3G8, or insoluble immune complexes was much less than after fMLP. Unlike [Ca2+]i rise induced by Fc receptor ligation, this small increase in IP3 was inhibited by pertussis toxin. These data demonstrated that the [Ca2+]i increase induced by Fc receptor ligation is not mediated by IP3. Immediate pretreatment of human polymorphonuclear neutrophils with optimal doses of fMLP also reduced subsequent increase in [Ca2+]i rise from thapsigargin, a sesquiterpene lactone tumor promoter that releases intracellular Ca2+ from IP3-sensitive stores without IP3 turnover. Similarly, to its effects on thapsigargin, fMLP inhibited the [Ca2+]i rise upon subsequent immune complex binding. Pretreatment of cells with immune complexes also prevented subsequent [Ca2+]i rise from thapsigargin and fMLP. These data demonstrate that IgG Fc receptor ligation and fMLP activation of human polymorphonuclear neutrophils use distinct signal transduction mechanisms to release Ca2+ from the same thapsigargin-sensitive intracellular pool. In contrast to fMLP, signal transduction for increased [Ca2+]i after Fc receptor stimulation does not involve a pertussis toxin-sensitive G protein, and is independent of IP3.

Adult↗