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PubMed1980

Interactions among rheumatoid synovial cells and monocyte-macrophages: production of collagenase-stimulating factor by human monocytes exposed to concanavalin A or immunoglobulin Fc fragments.

Adherent synovial cells (ASC) were obtained from minced synovium from patients with rheumatoid arthritis by dissociating the lining cells from the extracellular matrix and dispersing them with proteases. These cells produce high levels of latent collagenase in primary culture. With passage of ASC, collagenase levels decrease but can be stimulated by a soluble factor (MCF) released in vitro from cultured human blood monocyte-macrophages. Monocyte cultures exposed to aggregated immunoglobulin, Fc fragments of immunoglobulin or concanavalin A (Con A) increase production of MCF several-fold more than the control cultures. MCF production by monocytes exposed to Fab fragments does not differ from controls. Although aggregated immunoglobulin, Fc fragments, and Con A stimulate PGE2 synthesis and secretion by human monocytes, the effects on MCF production are not mediated by PGE2 since concentrations of indomethacin that completely block PGE2 production do not inhibit MCF production. These findings of increased production of MCF by monocytes in response to substances that probably exert their effects via surface receptors could be relevant in interpreting the in vivo role of immune complexes in diseases associated with connective tissue destruction.

Arthritis, Rheumatoid↗

PubMed1984

Radiation effects on cultured human monocytes and on monocyte-derived macrophages.

Prior to administration, leukocyte transfusions are commonly irradiated with up to 5,000 R to eliminate lymphocytes and thereby prevent graft-versus-host disease in the recipient. It has been widely believed that phagocytes are resistant to this irradiation. In a recent report, we noted that phagocyte oxidative metabolism was compromised during preparation of white cells for transfusion. As part of our effort to examine the basis for this inhibition of phagocyte function during white cell preparation, we assessed the effects of irradiation on the long-lived monocytes that have been shown to persist at inflammatory foci posttransfusion. Human monocytes were irradiated for up to 3 min, receiving 2,500-5,000 R. This irradiation damaged human monocytes, significantly decreasing their in vitro survival for the first 3 wk of culture (p less than 0.02, irradiated versus control survival), and growth as assessed by two-dimensional cell size measurements during the first 2 wk of culture (p less than 0.01, irradiated versus control growth). Despite smaller cell size, total cell protein was significantly increased over time in irradiated cultures (p less than 0.001, irradiated versus control total protein per cell). Extracellular release of lysozyme and beta-glucuronidase per cell was not affected by irradiation, but extracellular lactate dehydrogenase (LDH) release was significantly increased after irradiation (p less than 0.001, irradiated versus control LDH release). Irradiated monocytes killed Listeria monocytogenes at a slower rate than the nonirradiated controls (p less than 0.05, irradiated versus control rate of killing). Thus, the data indicate that irradiation in doses used to prevent graft-versus-host disease in leukocyte transfusion recipients has a deleterious effect on in vitro human monocyte survival and function.

Blood Bactericidal Activity↗

PubMed1980

Supressor monocytes in patients with systemic lupus erythematosus. Evidence of suppressor activity associated with a cell-free soluble product of monocytes.

Abnormal SLE mononuclear cell responses to PHA can be corrected by removal of adherent mononuclear cells. The present study demonstrates that cell-free supernatants from allogeneic adherent cell cultures inhibit lymphocyte response and that addition of indomethacin to cultures partly blocks the inhibitory effect of the resulting supernatant. Supernatants from SLE monocyte cultures suppressed allogeneic normal T cell responses by 36% (response in supernatant 33,515 +/- 3814 cpm, media control 51,947 +/- 3173 cpm) but normal monocyte culture supernatants did not suppress (48,384 +/- 4172 vs. 47,477 +/- 3221 cpm). Early (less than 24 hr) addition of indomethacin to monocyte cultures prevented elaboration of inhibitory material. In normals, indomethacin-treated supernatants were strikingly stimulatory (response 178% +/- 24 of control), whereas similarly treated supernatants of SLE monocyte cultures were not stimulatory (response 103% +/- 8 of control). The data indicate that a soluble inhibitor of lymphocyte blastogenesis is produced by SLE monocytes.

Adult↗

PubMed1982

Phagocytosis and intracellular killing by peripheral blood monocytes of patients with monocytic leukemia.

This article concerns a study on the endocytic functions of circulating monocytes from 12 patients with acute or chronic monocytic leukemia. The results show that phagocytosis and intracellular killing of Staphylococcus aureus are impaired in only two patients and that the opsonic activity of the serum of all patients is normal. With respect to the intracellular killing of ingested Staphylococcus aureus, an interesting phenomenon was found in that the cells of patients with monocytic leukemia proved to be in a state of activation, as shown by the finding that patients' monocytes with normal phagocytosis killed about 64% of the ingested bacteria in the absence of extracellular stimulation by serum factors. When extracellular serum was present, the mean killing index rose to only 69%. This is unlike the situation seen in monocytes from healthy donors, where no killing occurs in the absence of extracellular serum and extracellular stimulation by serum factors is mandatory for optimal intracellular killing.

Acute Disease↗

PubMed1995

A soluble gradient of endogenous monocyte chemoattractant protein-1 promotes the transendothelial migration of monocytes in vitro.

Chemokines secreted by endothelium may promote diapedesis of leukocytes by a gradient-dependent chemotactic mechanism or by stimulating random motility so that leukocytes transmigrate in a gradient-independent manner. Alternatively, chemokines may bind to endothelium and extracellular matrix to stimulate haptotactic migration. We first analyzed the role of the chemokine monocyte chemoattractant protein-1 (MCP-1) in the migration of human monocytes across untreated or IL-1-stimulated HUVEC monolayers cultured on human amnion. Then we further examined whether MCP-1-dependent transmigration occurred through a chemokinetic, chemotactic, or haptotactic mechanism. A neutralizing mAb against MCP-1 inhibited passage of monocytes across untreated or IL-1-stimulated HUVEC by 74 +/- 3% and 45 +/- 4%, respectively. Addition of MCP-1 itself to the apical compartment of unstimulated HUVEC/amnion cultures also reduced the transmigration of monocytes, in this instance by 73 +/- 9%. MCP-1 suppressed diapedesis only when present above the endothelium at a concentration equal to or greater than that endogenously deposited beneath the endothelium, and its inhibitory action could be overcome by addition of more concentrated MCP-1 below the HUVEC cultures. As much as 90% of the MCP-1 secreted into the underlying basement membrane and connective tissue could be washed out of HUVEC/amnion cultures; this procedure decreased transmigration by 69 +/- 4%. These data indicate that MCP-1 promotes transmigration of monocytes, but only when present in a gradient across endothelial monolayers. They further suggest that this gradient is predominantly soluble, rather than haptotactic.

Cell Movement↗

PubMed1995

Triggering of complement receptors CR1 (CD35) and CR3 (CD11b/CD18) induces nuclear translocation of NF-kappa B (p50/p65) in human monocytes and enhances viral replication in HIV-infected monocytic cells.

Monocyte/macrophages may harbor HIV in a nonproductive fashion for prolonged periods of time. Viral gene expression may be reactivated by stimulation of the cells with LPS or cytokines such as TNF-alpha in vitro. The effect of LPS and TNF-alpha is mediated by their ability to induce nuclear translocation of the DNA-binding heterodimer NF-kappa B (p50/p65), which binds to a specific sequence in the HIV-long terminal repeat. The present study demonstrates that triggering of complement receptors CR1 (CD35) and CR3 (CD11b/CD18) enhances viral replication in HIV-infected human monocytic cells. Monocytic cell lines and normal peripheral blood monocytes were infected with HIV-1 in vitro and cultured in the presence or absence of F(ab')2 fragments of monoclonal anti-CR1 or anti-CR3 Abs or with C3 fragments. Stimulation of CR1 or CR3 induces a two- to fourfold increase in the amount of cell-associated and released p24 Ag in cell cultures that was equivalent to that observed in control cultures triggered with LPS. We further observed that stimulation of CR1 or CR3 induces the nuclear translocation of NF-kappa B p50/p65 in infected cells. Translocation of NF-kappa B p50/p65 was also observed following stimulation of CR1 or CR3 of uninfected peripheral blood monocytes from HIV-seronegative donors. The amount of protein translocated was similar to that observed when cells were stimulated with rhTNF-alpha. TNF-alpha did not mediate the translocation of NF-kappa B p50/p65 induced by triggering of complement receptors. Taken together, these observations suggest that HIV gene expression may be activated in infected monocytes through interaction of the cells with complement-opsonized particles and that enhanced viral replication is associated with C3 receptor-mediated nuclear translocation of the NF-kappa B complex.

Biological Transport↗

PubMed1994

Structure/activity analysis of human monocyte chemoattractant protein-1 (MCP-1) by mutagenesis. Identification of a mutated protein that inhibits MCP-1-mediated monocyte chemotaxis.

Monocyte chemoattractant protein-1 (MCP-1) is a monocyte-specific chemoattractant and activator and is a member of the chemokine-beta family of cytokines. To identify regions of MCP-1 which are required for its biological activity, we constructed human MCP-1 mutants that were expressed in eukaryotic cells and tested for their ability to attract monocytes in vitro. Deletion of amino acids 2-8 destroyed activity, suggesting that the amino-terminal region is necessary for activity. Within the deleted region, mutation of aspartate 3 to alanine produced a protein with 9% of wild-type activity, whereas mutation of asparagine 6 to alanine produced a protein with 52.9% of wild-type activity. Mutation of amino acids within the first intercysteine loop yielded variable results. Changing tyrosine 28 to aspartate or arginine 30 to leucine each produced proteins with essentially no monocyte chemoattractant activity. The side chains of these amino acids are predicted to point into a putative receptor binding cleft, and these loss-of-function mutations are consistent with this model. Also consistent is the retention of 60% of wild-type activity after mutation of serine 27 to glutamine, since the side chain of serine 27 is predicted to point away from the binding cleft. However, mutation of arginine 24, which lies outside of this area, to phenylalanine produced a protein with only 5% of wild-type activity, suggesting more complex interactions. Truncations of the carboxyl terminus, as well as mutation of aspartate 68 to leucine, generated proteins with 10-20% of wild-type activity. (Another carboxyl-terminal insertional mutation demonstrated that O-linked carbohydrate in MCP-1 alpha may be added to a threonine in the carboxyl-terminal region.) These findings are consistent with a structural model of dimeric MCP-1 which is similar to interleukin-8, in which amino acids that point into a cleft between the two carboxyl-terminal alpha-helices of the subunits are important for receptor binding. In addition, however, amino acids at the amino terminus and others outside of the interhelical cleft are also essential for activity. The carboxyl-terminal alpha-helix is not required for signaling per se but is required for maximal specific activity. Finally, four mutant proteins partially inhibited the ability of wild-type MCP-1 to attract monocytes in vitro.(ABSTRACT TRUNCATED AT 400 WORDS)

Amino Acid Sequence↗

PubMed1993

IL-1 and tumor necrosis factor-alpha each up-regulate both the expression of IFN-gamma receptors and enhance IFN-gamma-induced HLA-DR expression on human monocytes and a human monocytic cell line (THP-1).

Stimulation of human blood monocytes (adherent mononuclear cells) and the monocytic cell line, THP-1, by IL-1 or TNF-alpha leads to the up-regulation of IFN-gamma receptors. Scatchard analysis using 125I-IFN-gamma revealed a twofold increase in the number of IFN-gamma receptors on THP-1 cells without an alteration in the affinity of the receptor. The potential functional significance of this induction of IFN-gamma receptors on monocytes and THP-1 cells was investigated by examining the effect of IFN-gamma on MHC class II Ag expression by these cells. Both IL-1 and TNF-alpha enhanced the IFN-gamma-induced HLA-DR expression (> twofold) and this effect was inhibited by antibody to IFN-gamma. In the case of human monocytes, IL-1 or TNF-alpha, each by themselves also increased HLA-DR expression, which was also abrogated by antibody to IFN-gamma. The data suggest that the immunopotentiating effects of IL-1 and TNF-alpha are mediated in part by enhancing IFN-gamma receptor expression on monocytes and macrophages. This presumably would increase the capacity of IFN-gamma to activate macrophages, enabling them to express HLA-DR and present Ag more effectively.

HLA-DR Antigens↗

PubMed1996

Infection by Candida albicans inhibits apoptosis of human monocytes and monocytic U937 cells.

Infectious microorganisms can differently induce or inhibit apoptosis of immunocompetent effector and host cells. In this study we examined the influence of an infection by Candida albicans (C. albicans) on programmed cell death of monocytic U937 cells and human monocytes. Basal and tumor necrosis factor alpha (TNF-alpha)-induced DNA fragmentation of U937 cells was significantly inhibited by an infection with C. albicans. Enhanced apoptosis of U937 cells, induced by TNF-alpha, caused a diminished candidacidal activity of the effector cells, whereas inhibition of apoptosis by granulocyte-macrophage colony-stimulating factor (GM-CSF) was paralleled by an intensified host defense. Pretreatment of U937 cells or monocytes with the cyclooxygenase blocker indomethacin completely abolished the reduction of DNA fragmentation induced by the yeast. Studying the underlying mechanisms we found that C. albicans induced formation of prostaglandin E2 (PGE2) by U937. Exogenous administration of PGE2 down-regulated apoptosis of U937 or human monocytes to a similar extent as did fungal infection. Activation of protein kinase A by the cAMP analogue 8-bromo-cAMP inhibited U937 apoptosis, as did PGE2. On the other hand, rp-cAMP, a blocker of the cAMP-dependent signal transduction, restored and elevated DNA fragmentation levels down-regulated by C. albicans. U937 cells expressed the bcl-2 protein but the infection with fungi or PGE2 treatment did not increase proto-oncogene expression. Monocytic effector cells may therefore strengthen the defense against C. albicans by an autocrine feedback regulation via a PGE2-dependent, cAMP-transduced inhibition of apoptosis.

Apoptosis↗

PubMed1997

Pre-operative neutrophil and monocyte activation state predicts post-operative neutrophil and monocyte function.

OBJECTIVE: To find out if the in vitro responses of neutrophils (PMN) and monocytes preoperatively can predict their activation postoperatively. DESIGN: Prospective open study. SETTING: Teaching hospital, Ireland. SUBJECTS: 46 Patients (32 men, 14 women, mean age 65 years, range 33-85) who were to undergo elective major vascular or gastrointestinal operations for benign (n = 18) or malignant (n = 28) diseases. INTERVENTIONS: Measurement by flow cytometry of functional (PMN and monocyte respiratory burst activity) and phenotypic (expression of PMN CD 11b adhesion receptors and monocyte CD14 receptors) markers of activation. MAIN OUTCOME MEASURES: Correlation between mean channel fluorescence (MCF) preoperatively and postoperatively. RESULTS: In 24 patients PMN respiratory burst activity was increased before operation and had decreased significantly (p < 0.01) on postoperative day 1 (high responders group). In the remaining 22 patients (low responders group) respiratory burst activity was low before operation and had increased significantly (p < 0.05) on postoperative day 1. PMN CD 11b activity followed a similar trend. Monocyte activity responded similarly (in the high group mean (SEM) MCF preoperatively was 69.14 (13.15) compared with 58.23 (10.8) on day 1, and in the low group the corresponding figures were 38.5 (7.01) and 8.43 (5.2). Expression of CD14 did not differ between the groups and was less postoperatively than preoperatively. The groups did not differ in age, sex, APACHE 11 scores, smoking habits or types of disease and there was no major infective complications in either group. CONCLUSION: There are two distinct patterns of PMN and monocyte responses to injury that are independant of age, sex and severity of operation. These may be associated with the degree of stress preoperatively or with genetic factors.

Adult↗

PubMed2005

Mechanical stretch induces monocyte chemoattractant activity via an NF-kappaB-dependent monocyte chemoattractant protein-1-mediated pathway in human mesangial cells: inhibition by rosiglitazone.

Hemodynamic abnormalities are important in the pathogenesis of the glomerular damage in diabetes. Glomerular macrophage infiltration driven by the chemokine monocyte chemoattractant protein-1 (MCP-1) is an early event in diabetic nephropathy. The thiazolidinedione rosiglitazone ameliorates albumin excretion rate in diabetic patients with microalbuminuria and has anti-inflammatory properties, raising the possibility of a relationship between its renoprotective and anti-inflammatory activity. Investigated was whether mesangial cell stretching, mimicking in vitro glomerular capillary hypertension, enhances MCP-1 expression and monocyte chemoattractant activity. The effect of the combination of stretch with high glucose on MCP-1 production was studied and, finally, the effect of rosiglitazone on these processes was assessed. Stretching of human mesangial cells significantly enhanced their monocyte chemoattractant activity. This effect was mediated by MCP-1 as it was paralleled by a significant rise in both MCP-1 mRNA and protein levels and was completely abolished by MCP-1 blockade. Combined exposure to both stretch and high glucose further increased MCP-1 production. Stretch activated the IkappaB-NF-kappaB pathway, and NF-kappaB inhibition, with the use of the specific inhibitor SN50, completely abolished stretch-induced MCP-1, indicating that stretch-induced MCP-1 was NF-kappaB dependent. The addition of rosiglitazone significantly diminished stretch-induced NF-kappaB activation, MCP-1 production, and monocyte chemotaxis. In conclusion, stretching of mesangial cells stimulates their monocyte chemoattractant activity via an NF-kappaB-mediated, MCP-1-dependent pathway, and this effect is prevented by rosiglitazone.

Cells, Cultured↗

PubMed1990

[Monocyte locomotion inhibiting factor (MLIF) produced by E. histolytica induces an increase of cAMP in human monocytes].

The supernatant fluid of axenically grown E. histolytica contains a factor (MLIF) which inhibits the locomotion of human monocytes (including chemotaxis) without affecting that of human polymorphonuclear leucocytes. Locomotion, like other cellular functions, is modulated by changes in intracellular cAMP and cGMP. The consensus--with some exceptions--is that while rises in cGMP accompany locomotion, an increase in cAMP (without a concomitant fall in -cGMP) occurs with inhibition of cellular movement. We measured by radioimmunoassay the cAMP concentration of human monocytes exposed to inhibitory concentrations of MLIF. A significant (p less than 0.005) rise in monocyte cAMP was found, comparable to that observed with the use of forskolin, a well known cAMP stimulator. The control studies using plain axenic medium, not only failed to reveal any rise in cAMP but disclosed a small, yet not significant drop in intracellular cAMP. These results suggest that MLIF (like other locomotion inhibitors, i.e. prostaglandins E1, A1 and isoproterenol) produces a significant increase in intracellular monocyte cAMP. This modification in intracellular signals may contribute to the inhibition in monocyte locomotion, an event during which an increase in pericentriolar microtubules has also been observed.

Animals↗

PubMed1997

Expression of monocyte chemotactic protein-3 in human monocytes exposed to the mycobacterial cell wall component lipoarabinomannan.

Monocyte chemotactic protein-3 (MCP-3) is a C-C chemokine which interacts with the CCR1, CCR2 (MCP-1) and CCR3 receptors and has a distinct spectrum of action. The present study was designed to assess whether mycobacterial components were able to induce expression and production of MCP-3 in human monocytes. Mycobacterial lipoarabinomannan (LAM) induced expression of MCP-3 mRNA in human peripheral blood mononuclear cells. The non-mannose-capped version of lipoarabinomannan (AraLAM) was considerably more potent than the mannose-capped version ManLAM or the simpler version phosphatidylinositol mannoside (PLM). Among mononuclear cells, monocytes were responsible for LAM-induced MCP-3 mRNA expression. Whole mycobacteria (Mycobacterium bovis BCG) strongly induced MCP-3 expression. Pretreatment with actinomycin D abolished LAM-induced MCP-3 expression, whereas cycloheximide only partially reduced the expression. LAM-induced MCP-3 expression was associated with the production of immunoreactive PTX3. Interleukin 10 (IL-10) and IL-13 inhibited the induction of MCP-3 by LAM. Thus mycobacterial cell wall components induced expression of MCP-3 in human monocytes. MCP-3, a chemokine active on mononuclear phagocytes, NK cells, T cells and dendritic cells, may be relevant to the induction and expression of immunity against mycobacteria.

C-Reactive Protein↗

PubMed1996

Human monocyte chemoattractant protein (MCP)-4 is a novel CC chemokine with activities on monocytes, eosinophils, and basophils induced in allergic and nonallergic inflammation that signals through the CC chemokine receptors (CCR)-2 and -3.

The chemokines are a large family of cytokines that regulate the complex and precise recruitment of immune cells into inflammatory foci. To fully appreciate their role in the pathogenesis of human diseases, the entire spectrum of chemokines, their receptors, their cellular targets, and mechanisms of regulation need to be delineated. Using eotaxin as a probe, we isolated a cDNA for a novel human beta (or CC) chemokine that, based on its biological and structural features, we have named monocyte chemoattractant protein (MCP)-4. Purified recombinant MCP-4 protein was a potent chemoattractant for monocytes and eosinophils and stimulated histamine release from basophils. MCP-4 induced a calcium flux in HEK-293 cells transfected with the monocyte selective MCP-1 receptor (CCR-2B) and the eosinophil selective eotaxin receptor (CCR-3), but not in the more widely expressed CCR-1 or CCR-5. This novel chemokine is expressed in TNF-alpha and IL-1 activated epithelial and endothelial cells in vitro, and in the epithelial mucosa of patients with both Th2-type allergic and Th1-type nonallergic sinusitis. Furthermore, both IFN-gamma and IL-4, products of Th1 and Th2 cells, respectively, synergized with TNF-alpha and IL-1 in inducing MCP-4 mRNA accumulation. These properties of MCP-4 offer a molecular explanation for the observed accumulation of monocytes, eosinophils and basophils in both Th1- and Th2-type immune responses.

Base Sequence↗

PubMed1997

Expression of monocyte chemotactic protein-3 in human monocytes and endothelial cells.

Monocyte chemotactic protein-3 (MCP-3) is a C-C chemokine which interacts with the CCR1, CCR2 (MCP-1) and CCR3 receptors and has a distinct spectrum of action. The present study was designed to investigate whether human endothelial cells (EC) and, by way of comparison, monocytes express MCP-3 and its regulation by pro- and anti-inflammatory cytokines. Unstimulated human umbilical vein EC and monocytes did not express MCP-3. Bacterial lipopolysaccharides (LPS), IL-1 and TNF induced low, but appreciable levels of MCP-3 transcripts. Interferon-gamma was a much weaker, but nevertheless active, inducer. MCP-3 transcripts were considerably less abundant than those for MCP-1. IL-4, IL-13 and IL-10 did not induce MCP-3 expression. These anti-inflammatory cytokines suppressed cytokine-induced MCP-3 expression in monocytes. In contrast, IL-4, IL-13 and IL-10 either did not affect or they amplified MCP-3 induction in EC. EC-produced MCP-3 may be important in the regulation of extravasation of receptor-expressing cells, including NK cells and eosinophils.

Cells, Cultured↗

PubMed1987

Peripheral blood and synovial fluid monocyte activation in inflammatory arthritis. I. A cytofluorographic study of monocyte differentiation antigens and class II antigens and their regulation by gamma-interferon.

Recent study of the expression of monocyte differentiation antigens (MAg) and HLA-DR on peripheral blood monocytes (PBM) has led to the recognition of resting and activated monocyte phenotypes. The former is identified by the expression of large amounts of MAg (i.e., Mo2 and 63D3) and small amounts of HLA-DR, while the latter is identified by the reverse. We studied the phenotypes of PBM and synovial fluid monocytes (SFM) of patients with chronic inflammatory arthritis and found that PBM were primarily resting and SFM were usually activated. In addition, we measured the degree of modulation of MAg and HLA-DR by gamma-interferon (gamma-IFN). Patient PBM reacted the same as PBM from normal individuals (i.e., MAg decreased and HLA-DR increased after exposure to gamma-IFN). However, in patient SFM, HLA-DR did not increase with exposure to gamma-IFN because expression was already maximal. Interestingly, MAg could still be down-regulated on gamma-IFN-treated SFM, even when expression began at a very low level (i.e., activated phenotype). This independent regulation of MAg and HLA-DR suggests that macrophage activating factors other than gamma-IFN may be responsible, in part, for the activated phenotypes observed.

Antigens, Differentiation↗

PubMed2003

All-trans retinoic acid down-regulates expression and function of beta2 integrins by human monocytes: opposite effects on monocytic cell lines.

All-trans retinoic acid (ATRA) plays an important role in the differentiation of malignant myeloid cells but its effects on primary leukocytes have been poorly investigated. We report here that ATRA negatively affects expression and function of leukocyte integrins that play a key role in monocyte adhesive interactions. As evidenced by flow cytometry, ATRA (at 1 microM) clearly and donor-independently suppressed the expression of all integrin chains investigated (CD11a, CD11b, CD11c, and CD18), most strikingly of CD11a. Down-regulation was detectable after 24 and maximal after 72-96 h. Reverse transcription-PCR analysis revealed diminished steady-state concentrations of alpha specific transcripts but not of the common beta chain, suggesting that heterodimer expression was predominantly regulated through alpha chains. Results obtained with blood-derived monocytes were in sharp contrast to those for the leukemic cell lines THP-1 and U937, both of which showed marked increase in all integrin subunits in response to ATRA. ATRA-pretreated monocytes displayed significantly diminished beta(2) integrin-dependent homotypic aggregation, and adhesion to stimulated endothelial cells (EC), while ATRA-pretreated monocytic cell lines showed the opposite behavior displaying markedly enhanced aggregation and CD18-mediated adhesion to EC. Therefore, the level of leukocyte integrins was obviously a decisive factor for these adhesive interactions irrespective of the cellular source. Collectively, our data indicate a striking difference between leukemic cell lines and normal hematopoietic cells with regard to ATRA responsiveness. By acting on key adhesive structures of normal leukocytes, ATRA mediates processes that may be of substantially broad range applying to inflammation and immunity in addition to differentiation and proliferation.

CD11 Antigens↗

PubMed1994

cDNA sequences encoding human fructose 1,6-bisphosphatase from monocytes, liver and kidney: application of monocytes to molecular analysis of human fructose 1,6-bisphosphatase deficiency.

Fructose 1,6-bisphosphatase deficiency is an autosomal recessive inherited disorder of gluconeogenesis. We could isolate cDNAs encoding human fructose 1,6-bisphosphatase from normal monocytes, liver and kidney, but not from normal lymphocytes. The cDNAs contained an open reading frame coding for 338 amino acids, and their nucleotide sequences in monocytes and liver were identical. G644C645 nucleotides in this sequence were the same as those of cDNA from HL-60 cells, although our result differed from a previous report (M. El-Maghrabi et al. (1993) J. Biol. Chem. 268, 9466-9472) on an alteration to C644G645 nucleotides in human liver cDNA resulting in a change of Gly-214 to Ala-214 in the enzyme. The Gly-214 (GGC) residue was therefore conserved in the enzymes hitherto isolated from humans and other animals. Analysis of monocytes in seven patients with fructose 1,6-bisphosphatase deficiency showed a DNA fragment with apparent normal size in two sisters but no detectable DNA fragment in the other five patients. Monocytes were thus useful as an alternative source for mRNA from human liver for the molecular analysis of fructose 1,6-bisphosphatase deficiency.

Alanine↗