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PubMed2000

Identification and characterization of differentially expressed mRNAs in HIV type 1-infected human T cells.

We used a novel differential display (DD) technique to identify host factors involved in virus replication, pathogenesis, and host response in HIV-1-infected T cells. Thirteen cDNA fragments differentially expressed in HIV-1NL4-3-infected MT-4 cells prior to the occurrence of specific apoptotic cell death were sequenced and identified. Two of seven elevated genes were identical to HIV-1 sequences and the other five were MIP-1alpha, ACTE-III, CD11c, arginase I, and CCR5. The six downregulated genes included prothymosin-a, Jaw-1, proteasome subunit XAPC7, splicing factor 9G8, GA17 protein, and an unknown mRNA. Northern blot and RT-PCR analyses confirmed the altered gene expressions in MT-4 cells as well as in another T cell line, MOLT-4. We also revealed that the amount of MIP-1alpha in culture supernatant of HIV-1-infected cells was increased by more than 15-fold relative to control cells, and the expression of its receptor CCR5 was cooperatively upregulated on the surface of these cells. Furthermore, the upregulation of CD11c after HIV-1 infection was slightly inhibited by blocking the MIP-1alpha-mediated signal transduction. These results indicate that genes altered on HIV-1 infection may be mutually organized and play an important role in HIV-1-induced pathogenesis.

CD4-Positive T-Lymphocytes↗
PubMed2001

An anti-inflammatory drug, propagermanium, may target GPI-anchored proteins associated with an MCP-1 receptor, CCR2.

Monocyte chemoattractant protein-1 (MCP-1) promotes the migration and activation of monocytes and plays a pivotal role in the development of chronic inflammation. Propagermanium (3-oxygermylpropionic acid polymer) has been used as a therapeutic agent against chronic hepatitis B in Japan. We report here that propagermanium specifically inhibits in vitro chemotactic migration of monocytes by MCP-1. Propagermanium did not inhibit binding of MCP-1 to a human monocytic cell line, THP-1 cells, or affect intracellular Ca(2+) mobilization or the cAMP concentration in MCP-1-treated THP-1 cells. The effect of propagermanium seems to require glycosylphosphatidylinositol (GPI)-anchored proteins, as cleavage of GPI anchors by phosphatidylinositol-phospholipase C (PI-PLC) eliminated the inhibitory activity of propagermanium. Anti-GPI-anchored protein antibodies, such as anti-CD55 and anti-CD59, reduced staining of C-C chemokine receptor 2 (CCR2) with an anti-CCR2 antibody against the N-terminus of CCR2 in a flow cytometric analysis, and these antibodies also selectively inhibited MCP-1-induced migration of THP-1 cells. Furthermore, under fluorescence microscopy, GPI-anchored proteins colocalized with CCR2 on THP-1 cells. These results suggest that propagermanium may target GPI-anchored proteins that are closely associated with CCR2 to selectively inhibit the MCP-1-induced chemotaxis, thus providing a mechanistic basis for the anti-inflammatory effects of the drug.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1992

Human p150,95 alpha-subunit: genomic organization and analysis of the 5'-flanking region.

LFA-1, Mac-1, and p150,95 comprise a family of cell-surface glycoproteins that mediate adhesive interactions of myeloid and lymphoid cells. These glycoproteins are heterodimers composed of a common beta-subunit and distinct alpha-subunits. The chromosomal gene for the alpha-subunit of p150,95 was isolated to provide a framework from which to study the mechanisms for expression of the gene. The gene spans 30 kb of DNA and contains 31 exons. In agreement with a previous report by Corbi et al. (1990), the exons were found to be divided into five groups separated by large introns. The extracellular domains are encoded in exons 2 through 30 while the transmembrane and cytoplasmic domains are encoded in exons 30 and 31. We have expanded these findings in a number of ways. The first exon contains the 5' untranslated region. The 2,163-bp 5'-flanking sequence contains the first intron and several putative transcriptional initiation sites preceded by two TATA sequences and two GC-like boxes. Additional sequence motifs for a variety of DNA-binding proteins are present and discussed. Fusions of the bacterial chloramphenicol acetyltransferase gene (CAT) to approximately 5.3 kb of 5'-flanking DNA and also to subcloned fragments of this region were constructed and transfected into the human promonocytic cell line, U937. CAT expression was inducible with phorbol-12-myristate-13-acetate (PMA) and full expression was dependent on the presence of intron 1 and sequences upstream from the 2,163-bp flanking DNA. Additionally, intron 1 and a region further upstream contain functional cis-acting sequences.

Base Sequence↗
PubMed1991

The expression of CD22 (Leu 14) and CD11c (LeuM5) in chronic lymphoproliferative disorders using two-color flow cytometric analysis.

The monoclonal antibodies (MoAbs) CD22 and CD11c recognize B-lymphocyte- and monocyte-associated antigens, respectively. Reports indicate that when these two MoAbs co-express, they represent a unique marker for hairy cell leukemia (HCL) although neither is specific for that disease. The authors evaluated the expression and diagnostic utility of CD22 and CD11C in specimens from 26 normal subjects, 29 patients, with various nonlymphoproliferative disorders (NLPDs), and 75 patients with different types of chronic lymphoproliferative disorders (CLDs) using two-color flow cytometric analysis of peripheral blood lymphocytes. Lymphocytes co-expressed CD22 and CD11c in less than or equal to 3% of the normal subjects and in less than or equal to 6% of the patients with NLPDs. These markers were expressed in greater than 10% of the lymphocytes of 46% (32/69) of the patients with B-cell CLDs: B-cell chronic-lymphocytic leukemia, 9/41; B-cell non-Hodgkin's lymphoma, 8/14; HCL, 11/11; B-cell lymphoproliferative disorder (NOS), 1/2; and B-cell prolymphocytic leukemia, 1/1. None (0/6) of the lymphocytes of patients with T-cell CLDs expressed greater than 10% CD22-positive (CD22+) or CD11c-positive (CD11c+) cells. The HCL cases demonstrated a unique CD22+CD11c+ fluorescence histogram pattern, distinct from other lymphoproliferative disorders, that was characterized by uniformly intense CD11c and CD22 fluorescence. Differences in the expression of the CD22+CD11C- and CD22+CD11C+ phenotypes between diagnostic groups were found, most notable was a paucity of CD22+CD11c+ cells in lymphocytes of patients with HCL. CD22 also had more variable expression than CD19 and HLA-DR in the cases of B-cell CLD. This study demonstrates that the CD22+CD11c+ phenotype is not unique to HCL but is a consistent feature of that disorder and that the immunofluorescence pattern of co-expression in HCL is diagnostically useful.

Antigens, CD↗
PubMed2001

Evidence for a role of ganglioside GM1 in antigen presentation: binding enhances presentation of Escherichia coli enterotoxin B subunit (EtxB) to CD4(+) T cells.

Successful antigen presentation by antigen-presenting cells is governed by a number of factors including the efficiency of antigen capture by cell-surface receptors, targeting to compartments of antigen processing, surface expression of MHC II-peptide complexes and presence of co-stimulatory signals. Ganglioside GM1 is an important component of membrane glycosphingolipids, and has been implicated in cell differentiation, apoptosis and signal transduction pathways. Using the B subunit of Escherichia coli enterotoxin (EtxB), a potent immunogen that binds GM1 with high affinity, and a non-binding mutant of EtxB, EtxB(G33D), we demonstrate that GM1 is intimately involved in several aspects of antigen presentation. Thus, GM1-mediated presentation of EtxB by B cells and CD11c(+) dendritic cells (DC) significantly enhanced the proliferation and cytokine expression of EtxB-specific CD4(+) T cells. Investigation regarding potential mechanisms revealed that EtxB binding directly augments the expression of MHC class II on B cells, and fractionation of B cells demonstrated that EtxB binding to GM1 results in rapid internalization and targeting to class II-rich compartments. GM1-mediated uptake of antigens and access to class II compartments in B cells can be exploited to significantly enhance the presentation of ovalbumin-conjugated to EtxB. These results demonstrate that GM1 can play an important role in antigen presentation via the MHC II pathway.

Animals↗
PubMed1998

Citrate anticoagulation does not correct cuprophane bioincompatibility as evaluated by the expression of leukocyte surface molecules.

BACKGROUND: Citrate, used for the anticoagulation of the extracorporeal dialysis circuit, reduces ionized calcium by chelation and has been claimed to attenuate dialyser membrane bioincompatibility. Dialysis with complement-activating cuprophane membranes is associated with leukopenia which has been related to an increase in adhesion molecule expression on the surface of circulating leukocytes. METHODS: The effect of citrate anticoagulation on the expression of CD11b, CD11c and CD45 on the surface of granulocytes and CD14 on monocytes during haemodialysis with cuprophane membranes, was evaluated by flow cytometric analysis. A comparison of standard heparin vs citrate was performed in 14 chronic haemodialysis patients. During citrate anticoagulation a calcium-free dialysate was used and citrate was infused to obtain a concentration of 4.3 mmol/l blood. The unchallenged 'baseline state' expression of the surface molecules and the increase after ex vivo stimulation with phorbol 12-myristate 13-acetate (delta-PMA) or formyl-methionyl-leucyl-phenylalanine (delta-fMLP) was studied. RESULTS: With heparin, as well as with citrate, a sharp fall in granulocyte and monocyte count was observed after 15 min of dialysis, followed by a recovery at the end of the session. The expression of CD11b, CD11c and CD45 on granulocytes increased markedly during cuprophane dialysis with a peak at 15 min; there were no differences in response between heparin and citrate anticoagulation. Delta-PMA and delta-fMLP for CD45, CD11c and CD14 showed a decrease during cuprophane dialysis vs t0; again there were no differences between heparin and citrate. CONCLUSION: We conclude that the use of citrate was not associated with reduced leukocyte activation as measured by the expression of surface molecules during cuprophane dialysis and that no effect on dialysis leukocytopenia could be registered.

Aged↗
PubMed1982

Limited chymotryptic cleavage of human C4-binding protein: isolation of a carbohydrate-containing core domain and an active fragment.

Human C4 binding protein (C4bp), which is a macromolecular weight (Mr 450,000-590,000) cofactor of C3b/C4b inactivator (I), is composed of 6 or 8 disulfide-linked polypeptide chains of Mr 75,000. Chymotrypsin cleaved C4bp into two major fragments; a large fragment of Mr 160,000, which contained carbohydrate chains and was composed of disulfide-linked polypeptide chains of Mr 25,000, and a small fragment of Mr 48,000, which was a single polypeptide chain and had the cofactor activity of C4bp. These results suggest that chymotrypsin liberates a functional domain-containing Mr 48,000 fragment from each subunit chain of C4bp and yields a core fragment derived from a disulfide-knot domain connecting each subunit chain of C4bp.

Carbohydrates↗
PubMed1995

A subset of macrophages located along the basement membrane ("lining cells") is a characteristic histopathological feature of psoriasis.

In this paper, we describe the immunophenotype and ultrastructure of a new macrophage subpopulation present in inflamed but not in normal human skin. In biopsy material from patients with psoriasis (n = 4), atopic dermatitis (n = 4), and positive patch test reactions (n = 4), spindle-shaped macrophages located along the basement membrane were detected staining positive for CD11c (LeuM5 high, Ki-M1 low), CD68 (Ki-M6 low), and Ki-M8 (low). This subpopulation was most prominent in psoriasis, where a median of 34 macrophages neighbored 100 basal keratinocytes, thus covering about 80% of the dermoepidermal junction. The numbers of atopic and positive patch test reactions were 11 and 13, respectively, accounting for about 20% of the dermoepidermal junction. Transmission electron microscopy revealed an electron-lucent nucleus with dense deposits of chromatin along the nuclear membrane. Interruptions of the integrity of the basement membrane neighboring these cells were also seen. We repeatedly observed parts of basal keratinocytes merging through these openings and macrophages exhibiting cytoplasmic extentions directed toward the porus. Our observations suggest vigorous interactions between macrophages and basal keratinocytes and support the hypothesis that these interactions are an important regulatory event in the pathogenesis of psoriasis.

Antigens, CD↗
PubMed1991

Role for specific complement phenotypes and deficiencies in the clinical expression of IgA nephropathy.

IgA nephropathy, the most commonly occurring type of chronic glomerulonephritis in individuals of European and Asian descent, exhibits marked heterogeneity of clinical signs and ultimate prognosis. Based upon their studies of regional clustering of the ancestors of related patients in eastern Kentucky, the authors have postulated the existence of an inherited disease susceptibility for IgA nephropathy. They examined serum concentrations of individual complement proteins and phenotypes for C3, C4A, C4B, and factor B (Bf) for related and unrelated patients with IgA nephropathy from Kentucky and for patients from the Mid-South region of Tennessee, Mississippi, and Alabama. In these populations, they have described partial complement deficiencies or specific phenotypes which may be associated with the disease. Their findings include the following: (1) partial deficiencies for C2, beta 1H (H), properdin (P), or C4 binding protein (C4BP) in four patients with end-stage renal disease, (2) an association between the C3*F allele with IgA nephropathy in the combined group of unrelated patients from Kentucky and the Mid-South, (3) the occurrence of C4B deficiency in two siblings with IgA nephropathy, and (4) an association between C4A deficiency and poor outcome in patients with IgA nephropathy diagnosed as adults. In addition, the related patients differ from the unrelated patients from Kentucky with respect to frequencies of Bf*F and the BfF (FF + FS + F1F + F1S) phenotype, suggestive of immunogenetic difference between these groups. Important functional differences exist between C4A and C4B isotypes and functional differences are also possible based upon C3 or Bf phenotype.(ABSTRACT TRUNCATED AT 250 WORDS)

Carrier Proteins↗
PubMed2000

Comparative studies of the colonic in situ expression of intercellular adhesion molecules (ICAM-1, -2, and -3), beta2 integrins (LFA-1, Mac-1, and p150,95), and PECAM-1 in ulcerative colitis and Crohn's disease.

A dysregulated local immune defense with a constant influx of leukocytes provides a basis for continuous intestinal inflammation in ulcerative colitis (UC) and Crohn's disease (CD). Cell adhesion molecules are pivotal for the migration of leukocytes from the circulation toward the colonic epithelium. A study quantifying the cells expressing intercellular adhesion molecules (ICAMs), beta2 integrins, and platelet-endothelial cell adhesion molecule-1 (PECAM-1) in the colon was performed to illustrate the leukocyte migration pathway in inflammatory bowel disease. Serial colonic sections (10 UC, 10 CD, and 10 controls) were stained immunohistochemically for ICAM-1, ICAM-2, ICAM-3, CD11a, CD11b, CD18, and PECAM-1. Cell adhesion molecule expression was evaluated quantitatively with reference to topographic localization. In UC, polymorphonuclear leukocytes (PMNs) in contact with the crypt epithelium and in crypt abscesses expressed CD11b. CD tissue was characterized by CD11a-, CD11c-, and ICAM-1-expressing cells. ICAM-1 was detected on endothelial cells, leukocytes, and apical parts of epithelial membranes, whereas ICAM-2 was expressed on basal epithelial membranes. Most infiltrating leukocytes expressed ICAM-3, whereas perivascular mononuclear cells expressed PECAM-1. Interestingly, the epithelial basement membrane in UC stained for CD18. In conclusion, CD11b, CD18, and ICAM-2 seem to be important for PMN transepithelial migration in UC, whereas CD11a, CD11c, ICAM-1, and ICAM-3 seem central in leukocyte locomotion and aggregation in CD. Differentiated upregulation of cell adhesion molecules is suggested to be essential for the diversities between UC and CD.

CD18 Antigens↗
PubMed2001

Propofol depressed neutrophil hydrogen peroxide production more than midazolam, whereas adhesion molecule expression was minimally affected by both anesthetics in rats with abdominal sepsis.

The treatment of sepsis may require mechanical ventilation of the lungs and sedation. Because neutrophils are the most important effector cells for protecting against sepsis, and propofol and midazolam are the most widely used anesthetics for sedation, we studied the effects of these two anesthetics on the neutrophil function during sepsis. Sepsis was induced in rats by cecal ligation and puncture. At either 4 h or 24 h after cecal ligation and puncture, blood and peritoneal neutrophils were obtained, incubated with the test anesthetics, and the hydrogen peroxide (H(2)O(2)) production and CD11b/c expression were determined by flow cytometry. In both early (at 4 h) and late (at 24 h) sepsis, propofol and midazolam depressed H(2)O(2) production by blood and peritoneal neutrophils at clinical concentrations. Propofol caused more depression than midazolam (P < 0.005). In both early and late sepsis, the effect of the anesthetics on the up-regulation of the stimulation-induced CD11b/c expression on blood neutrophils was minimal at clinical concentrations. If these results ultimately become clinically relevant, midazolam may be preferable to propofol for sedation during sepsis.

Anesthetics, Intravenous↗
PubMed2000

Dynamic expression of glial cell line-derived neurotrophic factor after cerebral ischemia.

The aim of this study was to understand the possible involvement of glial cell line-derived neurotrophic factor (GDNF) in rat brain ischemic injury by examining the expression and the cellular location of GDNF with molecular biological and morphological techniques. Expression of GDNF mRNA and protein was first increased as early as 2h after ischemia-reperfusion in peri-infarct cerebral cortex and striatum; it then declined, and showed a second increase at 72 h. Double staining confirmed that the earlier peak of GDNF expression was of neuronal origin and the later peak of glial origin. Considering the neurotrophic characteristics of GDNF, our findings suggest that elevated endogenous GDNF expression may have important roles in protection of ischemic injured neuronal cells.

Animals↗
PubMed1999

Depletion in blood CD11c-positive dendritic cells from HIV-infected patients.

OBJECTIVES: To quantify blood dendritic cells from HIV-positive patients and to study the expression of functional molecules, in relation to HIV viral load, CD4 cell counts and antiretroviral treatment. DESIGN AND METHODS: Three-colour flow cytometry analysis was used to quantify blood dendritic cells without previous isolation from whole blood and to study the expression of functional molecules (MHC class II, CD11c, CD83, CD86) by dendritic cells from 30 HIV-positive patients, 15 of whom were treated with combined antiretroviral therapy (viral loads from undetectable to 5.4 log copies/ml, CD4 cell counts 1-1895 cells/mm3) and 11 non-infected controls. RESULTS: The median proportion of blood dendritic cells from HIV-positive patients was significantly decreased when the plasma viral load was above 200 copies/ml: 0.2% (0.1-1.1, n = 19) compared with 0.4% (0.2-0.8, n = 11) in patients with undetectable viral load whether they were treated or not, and to 0.4% (0.2-1.3, n = 11) in controls (P = 0.02). A major decrease of the CD11c positive dendritic cells was observed in all HIV-positive samples, with only 18% (mean; range: 0.3-80%, median 4.2%) compared with 44% (11-70%, median 42%) of control dendritic cells (P = 0.0006). In contrast, the proportion of dendritic cells expressing CD86, was slightly higher in HIV-positive patients than in controls (P = 0.03). CONCLUSIONS: The decreased proportion of blood dendritic cells correlated with virus replication and the lack of dendritic cells expressing CD11c are the first evidence of strong dendritic cell alterations in HIV-positive patients. Although the proportion of blood dendritic cells are in the normal range in treated HIV-positive patients with undetectable viral load, the CD11c alterations persist indicating that antiretroviral therapy might only partly correct the alterations of the circulating dendritic cells.

Anti-HIV Agents↗
PubMed2001

Comparative loss and maturation of peripheral blood dendritic cell subpopulations in African and non-African HIV-1-infected patients.

OBJECTIVES: To quantify the percentage of the two major subpopulations of blood dendritic cells (DC) in HIV-1-seropositive Ugandan individuals infected with non-clade B viruses and compare this with that seen in clade B HIV-1 infected non-African individuals. DC maturation/activation status was also investigated via the expression of CD86. METHODS: The percentage of blood DC was quantified by using flow cytometry. DC were identified as the lineage (CD3, CD14, CD16, CD19, CD20, CD56)-negative, HLA-DR-positive population and the two major subpopulations were differentiated by CD11c expression. RESULTS: The percentage of blood DC was reduced significantly in HIV-1-seropositive African individuals when compared with controls (0.21 and 0.39% respectively). A similar reduction was also seen in non-African patients residing in the UK (0.19% compared with 0.36% for controls). However, there was no selective loss in either CD11c-positive or CD11c-negative subpopulations. The percentage of blood DC expressing CD86 was significantly greater in HIV-1-seropositive individuals when compared with controls and the increased expression was largely confined to CD11c-negative DC. CONCLUSIONS: Africans infected with non-clade B HIV-1 showed similar reductions in the percentage of blood DC to non-Africans infected with clade B viruses. There was no selective loss of either DC subpopulation, suggesting that the ability of DC to acquire and present antigens or to produce interferon-alpha may both be impaired in HIV-1 infection.

Adult↗
PubMedDate not supplied

Flt-3 ligand and sequential FL/interleukin-2 in patients with metastatic renal carcinoma: clinical and biologic activity.

Flt3 (fms-like tyrosine kinase 3) ligand, a cytokine that stimulates increases in the number of dendritic cells (DC) in vivo, has been shown to have antitumor activity in murine models via an immune-mediated mechanism. Therefore, we examined the clinical activity of this cytokine in patients with an immunologic-responsive cancer, metastatic renal cell carcinoma. Flt3 ligand (25 microg/kg subcutaneous) was administered daily for the first 14 days of a 28-day cycle. Although the treatment was well tolerated and was confirmed to induce expansion of lineage (Lin)-/HLA-DR+/CD11c+ myeloid DC and Lin-/HLA-DR+/CD123+ plasmacytoid DC, no clinical activity was observed. Reasoning that DC expanded by Flt3 ligand might potentiate the clinical activity of low-dose interleukin-2, a second study was conducted of sequential administration of 25 microg/kg of Flt3 ligand daily for 7 days was followed by 11 x 10(6) IU of subcutaneous interleukin-2 for 4 consecutive days x 4 weeks. In this study, increased numbers of circulating DC were again observed, which was followed by increased numbers of activated T cells, confirming a biologic effect of each cytokine. However, toxicity and clinical efficacy were similar to what has been seen with low-dose interleukin-2 alone, with two minor responses observed. These results demonstrate that Flt3 ligand, although capable of inducing expansion of circulating myeloid and plasmacytoid DC in patients with metastatic renal cell carcinoma, lacks significant clinical activity at the doses and schedules examined.

Adult↗
PubMed1998

Enhancement of peritoneal leukocyte function by granulocyte colony-stimulating factor in rats with abdominal sepsis.

OBJECTIVE: To investigate the therapeutic effects of granulocyte colony-stimulating factor (G-CSF) on the functional activities of circulating and peritoneal neutrophils during intra-abdominal sepsis. DESIGN: Placebo, controlled study, using a rat model of intra-abdominal sepsis. SETTING: Animal research facility. SUBJECTS: Male specific pathogen-free Sprague-Dawley rats. INTERVENTIONS: Abdominal sepsis was produced in rats by cecal ligation and puncture. The control animals received a sham operation. G-CSF (subcutaneous injection at 50 microg/kg) or vehicle (100 microL of 5% dextrose) treatment was initiated at 1 hr after cecal ligation and puncture or sham operation and repeated at 12-hr intervals thereafter. MEASUREMENTS AND MAIN RESULTS: Six hours after cecal ligation and puncture, CD11b/c and CD18 expression on circulating neutrophils was significantly up-regulated when compared with those in the sham operated control animals. Peritoneal neutrophils exhibited a further up-regulation of these adhesion molecules than did the circulating neutrophils. A sustained up-regulation of CD11b/c and CD18 was found in peritoneal neutrophils even at 24 hrs after cecal ligation and puncture. G-CSF treatment increased CD11b/c expression on circulating neutrophils in 6-hr sham-operated rats, but did not further up-regulate CD11b/c or CD18 expression on circulating or peritoneal neutrophils in cecal ligation and puncture rats. Phagocytic activities of circulating neutrophils assessed by uptake of fluorescent latex microspheres were lower in 24-hr cecal ligation and puncture rats when compared with the sham-operated controls. G-CSF treatment prevented this inhibition. Furthermore, G-CSF enhanced the phagocytic activities of peritoneal neutrophils in both 6- and 24-hr cecal ligation and puncture rats when compared with those of the vehicle-treated animals. Spontaneous hydrogen peroxide generation by circulating neutrophils was increased in 6-hr cecal ligation and puncture rats, but not in 24-hr cecal ligation and puncture rats. Peritoneal neutrophils exhibited an inhibition of phorbol myristate acetate-stimulated hydrogen peroxide generation. G-CSF treatment did not up-regulate neutrophil hydrogen peroxide generation. CONCLUSIONS: Circulating and peritoneal neutrophils exhibit marked polymorphism in their functional activities during the host response to abdominal sepsis. G-CSF treatment significantly enhanced the phagocytic function of both circulating and peritoneal neutrophils which may be one mechanism underlying its protective effect in abdominal sepsis.

Abdomen↗
PubMed1996

Protein tyrosine kinase activity and the influence of gender in phagocytosis and tumor necrosis factor secretion in alveolar macrophages and lung-recruited neutrophils.

The role of tyrosine phosphorylation in endotoxin-induced phagocytic and tumor necrosis factor secretory responses was studied in rat alveolar macrophages and lung-recruited neutrophils. Exploration of sexual dimorphism in some aspects of these functions was also a specific aim. Male and female rats were injected intratracheally with endotoxin or saline. Two and a half hours later the animals were subjected to bronchoalveolar lavage, and alveolar macrophages and lung-recruited neutrophils were isolated. Circulating neutrophils of endotoxin-treated rats were also isolated at this time. Phagocytosis and CD11b/c and CD18 expression were measured by flow cytometry; tumor necrosis factor was measured with a cytotoxicity assay. Using the protein tyrosine kinase inhibitor AG126 and phosphotyrosine immunoblotting, we demonstrated that tyrosine phosphorylation is an important signaling pathway in the activation of these cells by endotoxin and that it is coupled to phagocytosis and tumor necrosis factor secretion, but not to beta 2 integrin expression. Conditioned medium of alveolar macrophages of endotoxin-injected rats upregulates phagocytosis by blood neutrophils of naive rats and this upregulating activity is tyrosine phosphorylation dependent. The substrates for tyrosine phosphorylation are different in alveolar macrophages and lung neutrophils, as are their sensitivities to AG126. Significant gender differences exist in the modulation of phagocytosis by inhibition of tyrosine phosphorylation and in tumor necrosis factor secretion by endotoxin-stimulated alveolar macrophages.

Animals↗