Hans-Dieter Flad

Research Center Borstel, Borstel, Lower Saxony, Germany

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Publications (22)90.84 Total impact

  • Hans-Dieter Flad, Ernst Brandt
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    ABSTRACT: The identification of chemokines in blood platelets has strengthened our view of these cells as participants in immune host defense. Platelet chemokines representing prestored and rapidly releasable proteins may play a major role as first-line inflammatory mediators. This is evident from their capability to recruit early inflammatory cells such as neutrophil granulocytes and monocytes and even to exhibit direct antimicrobial activity. However, insight is growing that platelet chemokines may be also long-term regulators, e.g., by activating T lymphocytes, by modulating the formation of endothelium and even thrombocytopoiesis itself. This review deals with the individual and cooperative functionality of platelet chemokines, as well as their potential as a basis for therapeutic intervention in the pathology of inflammation, infection, allergy and tumors. Within this context, therapeutic strategies based on the use of antibodies, modified chemokines, chemokine-binding proteins and chemokine receptor antagonists as well as first clinical studies will be addressed.
    Cellular and Molecular Life Sciences CMLS 03/2010; 67(14):2363-86. · 5.62 Impact Factor
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    ABSTRACT: Monocyte/macrophage-mediated cytotoxicity requires the generation of activated oxygen radicals, which can be measured by chemiluminescence (CL). To investigate whether natural killer (NK) cell activity required activated oxygen species, both cytotoxicity against K562 target cells and CL were measured in cell populations of human peripheral blood. The following results were obtained: (a) Peripheral blood mononuclear cells (MNC) showed NK activity and a response in CL, which could be induced by viable or paraformaldehyde-fixed K562 target cells as well as by latex particles, (b) Both T cells and non-T cells exhibited NK activity, but T cells gave no K562- or latex-induced CL responses, (c) Depletion of phagocytic cells from MNC abolished CL, but only marginally affected NK activity, (d) Reconstitution of phagocyte-depleted MNC with adherent cells revealed a superadditive enhanced CL response, but had no augmenting effect on NK activity, (e) Phagocyte-depleted cell populations, enriched for NK activity by density gradient centrifugation, did not respond in K562- and latex-induced CL. (f) MNC, highly enriched for NK activity by cell sorting with a cytofluorograf using the fluorescein isothiocyanate-labeled monoclonal antibody anti-Leu-11a, responded only with reduced CL, whereas the NK activity was enriched up to 45-fold. From these results it is concluded that NK cell-mediated cytolysis of K562 target cells and K562-induced CL are not functionally correlated, but represent properties of two distinct cell populations, namely NK cells and monocytes.
    European Journal of Immunology 11/2005; 14(7):634 - 639. · 4.97 Impact Factor
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    ABSTRACT: Intracellular persistence of mycobacteria may result from an intricate balance between bacterial replication and signaling events leading to antimicrobial macrophage activities. Using human monocyte-derived macrophages, we investigated the relevance of mitogen-activated protein kinase activation for the growth control of Mycobacterium avium isolates differing in their abilities to multiply intracellularly. The highly replicative smooth transparent morphotype of M. avium strain 2151 induced significantly less p38 and extracellular signal-regulated kinases 1 and 2 (ERK1/2) phosphorylation than the smooth opaque morphotype of the same strain, which was gradually eliminated from macrophage cultures. Inhibition of the p38 pathway by highly specific inhibitors did not significantly affect mycobacterial replication within macrophages, regardless of the in vitro virulence of the M. avium strain. However, repression of the ERK1/2 pathway further enhanced intracellular growth of highly replicative M. avium strains, although it did not increase survival of the poorly replicating M. avium isolate. Inhibition of the ERK1/2 pathway resulted in decreased tumor necrosis alpha (TNF-alpha) secretion irrespective of the virulence of the M. avium isolate used for infection, revealing that TNF-alpha could have been only partially responsible for the control of intracellular M. avium growth. In conclusion, ERK1/2- and TNF-alpha-independent pathways are sufficient to limit intramacrophage growth of less-virulent M. avium strains, but early ERK1/2 activation in infected macrophages is critically involved in controlling the growth of highly replicative M. avium strains.
    Infection and Immunity 10/2002; 70(9):4961-7. · 4.07 Impact Factor
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    ABSTRACT: In this study, we have examined the major platelet-derived CXC chemokines connective tissue-activating peptide III (CTAP-III), its truncation product neutrophil-activating peptide 2 (CXC chemokine ligand 7 (CXCL7)), as well as the structurally related platelet factor 4 (CXCL4) for their impact on neutrophil adhesion to and transmigration through unstimulated vascular endothelium. Using monolayers of cultured HUVEC, we found all three chemokines to promote neutrophil adhesion, while only CXCL7 induced transmigration. Induction of cell adhesion following exposure to CTAP-III, a molecule to date described to lack neutrophil-stimulating capacity, depended on proteolytical conversion of the inactive chemokine into CXCL7 by neutrophils. This was evident from experiments in which inhibition of the CTAP-III-processing protease and simultaneous blockade of the CXCL7 high affinity receptor CXCR-2 led to complete abrogation of CTAP-III-mediated neutrophil adhesion. CXCL4 at substimulatory dosages modulated CTAP-III- as well as CXCL7-induced adhesion. Although cell adhesion following exposure to CTAP-III was drastically reduced, CXCL7-mediated adhesion underwent significant enhancement. Transendothelial migration of neutrophils in response to CXCL7 or IL-8 (CXCL8) was subject to modulation by CTAP-III, but not CXCL4, as seen by drastic desensitization of the migratory response of neutrophils pre-exposed to CTAP-III, which was paralleled by selective down-modulation of CXCR-2. Altogether our results demonstrate that there exist multiple interactions between platelet-derived chemokines in the regulation of neutrophil adhesion and transendothelial migration.
    The Journal of Immunology 10/2002; 169(5):2602-10. · 5.52 Impact Factor
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    ABSTRACT: Monocytes/macrophages undergo apoptosis and are in contact with apoptotic cells both in vitro and in vivo. The data show that monocytes undergoing spontaneous apoptosis in vitro change their cytokine production profile. We demonstrate that the lipopolysaccharide (LPS)-induced production of interleukin-10 (IL-10) is up-regulated, while production of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) is either not affected or reduced. These differences seen both at the protein and mRNA level directly correlate with the appearance of apoptotic cells in the culture. Flow cytometry analysis using double staining, surface with annexin V and intracellular with anti-IL-10, suggested that annexin V-negative monocytes are the predominant source of IL-10. Analysis of sorted populations of monocytes indicated that the increase in IL-10 synthesis appears to result from direct interactions between non-apoptotic and apoptotic cells at the time of stimulation. Also non-apoptotic, freshly isolated monocytes produced more IL-10 upon stimulation with LPS, Staphylococcus aureus or zymosan when apoptotic neutrophils were added to the culture. In contrast, monocyte-derived macrophages did not produce more IL-10 in the presence of apoptotic neutrophils. Finally, we found that the presence of apoptotic monocytes in the culture may influence specific immune responses. The data show that in the presence of annexin V-positive monocytes CD4-positive memory T cells produce less IFN-gamma upon stimulation with purified protein derivative of tuberculin, which could be partially reversed by anti-IL-10 neutralizing antibodies. We conclude that these findings might illustrate the mechanisms operating within an inflammatory site and play an important immunoregulatory role during the resolution of inflammation and specific immune responses.
    European Journal of Immunology 08/2002; 32(7):2011-20. · 4.97 Impact Factor
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    ABSTRACT: Platelet factor 4 (PF-4), a platelet-derived CXC chemokine, has been shown to induce the differentiation of monocytes into a subset of macrophages that lack the expression of HLA-DR Ag. This suggests a potential role for PF-4 in the modulation of monocyte-dependent T cell activation. Using an Ag-specific stimulation model in which T cells were cocultured with monocytes in the presence of recall Ags, we could show that under these conditions PF-4-treatment caused a strong decrease of T cell proliferation as well as of IFN-gamma release. However, inhibition of T cell functions such as proliferation, IL-2 release, and IL-2 mRNA production did also occur when isolated T cells were activated in the absence of monocytes with immobilized Abs directed against CD3 in combination with cross-linked anti-CD28 Abs. The effect could be reversed when low concentrations of exogenous IL-2 instead of anti-CD28 were used as a costimulus in combination with anti-CD3 Abs. Further evidence for direct modulation of T cell function by PF-4 was obtained by the detection of specific binding sites for the chemokine on the surface of these cells. Taken together, our results show that specific binding of PF-4, resulting in the down-regulation of the IL-2-release correlates with the inhibition of functions in activated T cells.
    The Journal of Immunology 08/2002; 169(2):770-7. · 5.52 Impact Factor
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    ABSTRACT: During early inflammation, the chemoattractants neutrophil-activating peptide-2 (NAP-2), platelet-activating factor (PAF), and complement component C5a are rapidly generated within the vasculature and potently induce effector functions in neutrophils, such as chemotaxis and degranulation. We investigated whether these mediators would cross-desensitize each other's activities on isolated neutrophils. We demonstrate that NAP-2 and C5a desensitize degranulation of neutrophils in response to PAF. However, whereas C5a-mediated desensitization correlated with the downregulation of PAF binding sites on neutrophils, NAP-2 did not regulate PAF receptors, nor did it modulate their calcium signaling. In further contrast to C5a, which desensitized PAF-induced neutrophil chemotaxis, NAP-2 did not affect the chemotatic response to PAF. These observations indicate that NAP-2 mediates selective desensitization of PAF-induced neutrophil degranulation by a mechanism downstream from PAF receptors, still allowing migration toward PAF. Thus, a role for NAP-2 may be to limit PAF-dependent vascular tissue damage by preventing degranulation of neutrophils without affecting their migration into the inflamed tissue.
    Journal of Interferon & Cytokine Research 03/2002; 22(2):257-67. · 3.30 Impact Factor
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    ABSTRACT: Human monocytes (Mo) consist of a major subset of Fcgamma-receptor I (CD64)-positive typical low accessory phagocytes, and a minor CD64(-) DC-like subset with high T cell-accessory and IFN-alpha-releasing activity. Both populations also differentially express CD16 (Fcgamma-receptor III). Double labeling with anti-CD64 and anti-CD16 mAb, as performed here, identified four different subsets. The CD64(-) subset consists of CD64(-) / 16(+) cells with high antigen-presenting cell (APC) function and macrophage-like phenotype, and a CD64(-) / 16(-) subset of less active APC but which exhibits a higher mixed lymphocyte reaction (MLR) stimulating and IFN-alpha-producing capacity, possibly resembling plasmacytoid dendritic cell type II (DC2) blood precursors. As well as the majority of CD64(+) cells that appeared CD64(+) / 16(-) and represent typical low-accessory, CD14(high) Mo, we could identify and describe a novel minor subset of CD64(+) / 16(+) cells which is unique in combining typical DC and Mo characteristics in the same cell. These are high IL-12 production, high accessory capacity for antigen- or allogen-activated lymphocytes, and high expression of HLA-DR, CD86, and CD11c.
    European Journal of Immunology 02/2001; 31(1):48-56. · 4.97 Impact Factor
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    ABSTRACT: Lipopolysaccharide (LPS), also known as endotoxin, is a compound of the cell wall of Gram-negative bacteria, which has been demonstrated to induce inflammatory reactions in vitro as well as in vivo, including lethal shock. A great number of different cells have been documented to be reactive to LPS, e.g. monocytes/macrophages, vascular cells, polymorphonuclear cells, and even B lymphocytes. We have now established that T lymphocytes could also contribute to an inflammatory reaction to LPS. LPS is a potent inducer of human T-lymphocyte proliferation and cytokine production. The activation of T lymphocytes by LPS requires direct cell-to-cell contact with viable accessory monocytes. This interaction was found to be MHC-unrestricted, but strongly dependent on costimulatory signals provided by B7/CD28 interactions. The frequency of responding T lymphocytes is less than 1:1000. A very exciting finding was that not only monocytes, but also CD34+ hematopoietic stem cells, which circulate in peripheral blood in very low frequency, exert essential accessory cell activity during stimulation of T lymphocytes by LPS. In contrast, the response of T lymphocytes to conventional recall antigens is not controlled by blood stem cells. These conclusions are based on the observation that depletion of CD34-positive blood stem cells resulted in a complete loss of LPS-induced T-lymphocyte stimulation. Addition of CD34-enriched blood stem cells led to a recovery of reactivity of T lymphocyte to LPS. The characteristics of T-lymphocyte activation indicate that LPS is neither active as a mitogen, or as a superantigen, or as a classical antigen, but may activate T lymphocyte through a new, so far undescribed, mechanism. Furthermore, the involvement of hematopoietic blood stem cells in the activation of T lymphocytes by LPS demonstrates a role of these cells in inflammatory and immunological events.
    Toxicology 12/2000; 152(1-3):37-45. · 4.02 Impact Factor
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    ABSTRACT: We studied 32 HIV-seronegative patients with pulmonary disease caused by nontuberculous mycobacteria (NTM). Immunologic studies included lymphocyte subset analysis by flow cytometry, measurement of interferon- (IFN-) and tumor necrosis factor- (TNF-) production followingin vitro stimulation of diluted whole blood (DWB) and peripheral blood mononuclear cells (PBMC) by phytohemagglutinin (PHA), anti-CD3 as well as purified protein derivative of tuberculin (PPD), and in four cases with different amounts of the very mycobacterium, which caused disease in these patients. Data were compared to those of 30 HIV-seronegative patients with disease byMycobacterium tuberculosis (MTb). Following -CD3-stimulation of PBMC, NTM patients showed lower IFN-(P and lower TNF-(P For a subgroup of tuberculin skin test-positive NTM patients we found significantly lower PPD-induced IFN- releases in cultured DWB(P and PBMC(P compared to MTb patients. Data for PPD-induced TNF- release for this subgroup were also significant(P andP respectively). The four NTM patients with poor PPD-induced IFN- response hardly showed increased cytokine production on stimulation with their specific mycobacterium. The lower production capacity of IFN- and TNF- of NTM patients compared to the MTb patients points to an immunologic imbalance forming the basis for their increased susceptibility to pulmonary infections by nontuberculous mycobacteria.
    Journal of Clinical Immunology 10/2000; 20(6):445-452. · 3.38 Impact Factor
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    ABSTRACT: Activation of myeloid cells by lipopolysaccharide (LPS) is a key event in the development of gram-negative sepsis. One crucial step within this process is the binding of LPS to CD14. CD14 is a glycosylphosphatidylinositol (GPI)-anchored membrane protein requiring at least one additional membrane-spanning molecule for signal transduction. It is not clear whether the function of CD14 is to merely catalyze LPS binding, followed by the interaction of LPS with the signal transducer, or whether CD14 has a more specific function and may be a part of the signaling complex. To address this question we generated Chinese hamster ovary (CHO) cells expressing a human GPI-anchored form of LPS-binding protein (mLBP) to substitute for CD14 as LPS acceptor molecule. By comparison of CHO / mLBP with CHO / vector and CHO / CD14 cells we found that expression of GPI-linked LBP results in an enhanced binding of LPS but not in an increase in cell activation as determined by translocation of NF-κB. Furthermore, excess of recombinant soluble LBP resulted also in increased LPS binding without affecting NF-κB translocation. These data show that LPS binding alone is not sufficient to induce signaling. We conclude that CD14 is more than a catalyst for LPS binding: it seems to be directly involved in LPS signaling and thus appears to be an essential part of the signaling complex.
    European Journal of Immunology 01/2000; 30(1):211-216. · 4.97 Impact Factor
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    ABSTRACT: Phagocytosis and killing of microorganisms by reactive oxygen radicals are important defence mechanisms of the immune system and it was shown that human monocytes (MO) are heterogeneous in exerting these functions. Previously, we described that human peripheral blood MO consist of a major subset of Fcγ-receptor-I (CD64)-positive cells exhibiting low accessory cell capacity but high phagocytic activity, and a minor subset of CD64-negative cells with dendritic cell (DC)-like high T cell accessory cell capacity but low phagocytic capacity. Recently, we could show that each subset itself further differs in the expression of the Fcγ-receptor-III (CD16) and T cell accessory activities resulting in four different subsets: two CD16+subsets (CD64+or CD64-) with high T cell stimulation capacity and two CD16-subsets (CD64+or CD64-) with low accessory activities. In the present study we demonstrate that these subsets also differ in their ability to phagocytose opsonized bacteria (S. aureusandE. coli) and in the generation of reactive oxygen species. Both CD64+subsets (CD16+or CD16-) exhibit high phagocytic activity accompanied by intracellular superoxide induction. Luminal-dependent (mainly myeloperoxidase (MPO)-mediated) chemiluminescence (CL) response to latex and FMLP (formylmethionylleucylphenylalanine) was also high in these cell populations. Phagocytic activity and modest CL response was shown in CD64-/CD16+but not in CD64-/CD16-cells, indicating that each subset except for CD64-/CD16-cells may engulf bacteria and exhibit MPO activity. Taken together, these data demonstrate further heterogeneity of peripheral blood MO in both, phagocytic activity and generation of reactive oxygen species indicating differences between the four subsets in this kind of defence mechanisms against pathogens.
    Immunobiology 01/2000; 202(1):42-50. · 2.81 Impact Factor
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    ABSTRACT: We have analyzed the HLA-DRB1 alleles and -308 TNF-alpha gene polymorphism in 78 sarcoidosis patients and 50 controls. The sarcoidosis group as a whole did not show any significant correlation with the TNF-A or the HLA-DR alleles compared to the control group. However, the patient subgroups of Löfgren and non-Löfgren sarcoidosis exhibited significant allele associations. In the Löfgren patient group, the TNF-A2 and the HLA-DR3 alleles were represented significantly higher, with a highly significant relative risk resulting from the presence of the TNF-A2 or the HLA-DR3 allele or both. In the non-Löfgren patient group, the phenotype expressing HLA-DR2 and lacking TNF-A2 was significantly higher than in the Löfgren patient group. Due to these significant genetic differences in the subgroups of Löfgren and non-Löfgren sarcoidosis patients, we conclude that the genotyping of these two loci (-308 TNF-alpha promoter polymorphism and HLA-DR) may be of prognostic value for the course of disease in sarcoidosis.
    European cytokine network 07/1999; 10(2):143-6. · 1.90 Impact Factor
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    ABSTRACT: The prerequisites for the initiation of pathophysiological effects of endotoxin (lipopolysaccharide [LPS]) include binding to and possibly internalization by target cells. Monocytes/macrophages are prominent target cells which are activated by LPS to release various pro- and anti-inflammatory mediators. The aim of the present study was to establish a new method to determine the binding and internalization rate of different LPS chemotypes by human monocytes and to correlate these phenomena with biological activity. It was found that membrane-bound LPS disappears within hours from the surface being internalized into the cell. Further, a correlation between the kinetics of internalization and the length of the sugar chain as well as an inverse correlation between the time course of internalization and LPS hydrophobicity was revealed. Comparison of the internalization kinetics of different LPS chemotypes with kinetics of tumor necrosis factor alpha release and kinetics of oxidative burst did not reveal any correlation of these parameters. These findings suggest that cellular internalization of and activation by LPS are mechanisms which are independently regulated.
    Infection and Immunity 06/1999; 67(5):2515-21. · 4.07 Impact Factor
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    ABSTRACT: The activation of immunocompetent cells by lipopolysaccharide (LPS) during severe Gram-negative infections is responsible for the pathophysiological reactions, possibly resulting in the clinical picture of sepsis. Monocytes recognize LPS mainly through the LPS receptor CD14, however, other cellular binding structures have been assumed to exist. In previous studies, we have described an 80-kDa LPS-binding membrane protein (LMP80), which is present on human monocytes as well as endothelial cells. Here we demonstrate that LMP80 is widely distributed and that it formes complexes together with LPS and sCD14. Furthermore, we report on the biochemical purification of LMP80 and its identification as decay-accelerating factor, CD55, by amino acid sequencing and cloning techniques. Our results imply a new feature of CD55 as a molecule which interacts with LPS/sCD14 complexes. However, the involvement of CD55 in LPS-induced signaling remains to be elucidated.
    FEMS Immunology & Medical Microbiology 02/1999; 23(3):259 - 269. · 2.68 Impact Factor
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    ABSTRACT: In 1885 Louis Pasteur was the first to propose that the human immune system may be influenced by microorganisms. A large body of data has since been accumulated proving this assumption to be correct. Bacteria constitute the main constituents of the microbial flora of the human digestive tract and compounds of the bacterial cell wall have been shown to play an important role in the interaction of microbes with higher organisms. These components include peptidoglycan (PG) and lipopolysaccharide (LPS) of Gram-negative bacteria. Both types of molecules are potent activators of the human immune system and exert their activity through the induction of endogenous mediators which are endowed with biological activity. This review focuses on the structure and activity of LPS and PG and illustrates how these bacterial factors stimulate the immune cells resulting in desired physiological or dramatic pathophysiological responses of the host organism.
    International Journal of Food Microbiology 06/1998; · 3.43 Impact Factor
  • Microbial Drug Resistance - MICROB DRUG RESIST. 01/1998; 4(1):37-44.
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    ABSTRACT: Multinucleated giant cells (MGCs) are a key feature of granulomas. They have been studied with respect to the mechanism and regulation of their formation, but the function of these cells still remains elusive. A new method for the in vitro generation of granulomas was developed and characterized in which L3 larvae of Nippostrongylus brasiliensis, as a target for the cellular response, were co-incubated with human mononuclear blood cells. The development of epithelioid cells and MGCs was observed and single isolated MGCs were analysed by the reverse transcriptase polymerase chain reaction method. The presence of tumour necrosis factor alpha (TNFα), interleukin-1 beta (IL-1β), interleukin-6 (IL-6), and inducible nitric oxide synthase (iNOS) transcripts in MGCs was demonstrated. It is proposed that MGCs in the granuloma model may in part represent an active cellular constituent involved in granuloma formation and turnover and in the destruction of the irritant. © 1997 John Wiley & Sons, Ltd.
    The Journal of Pathology 01/1997; 182(1):99-105. · 7.59 Impact Factor
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    ABSTRACT: We report an experimental study, by means of ps time-resolved luminescence correlations, of the free carrier relaxation in type II InP/AlInAs heterostructures. The decay times are measured in the energy range corresponding to the spatially indirect electron-hole recombination and at low excitation power in order to avoid band-filling effects. These times are in the range of a few tens of ps. They are much shorter than the decay time of the spectrally integrated and correspond to the plasma thermalization times. From the experimental data, the presence of a large amount of traps or carriers due to a residual doping is inferred and it is shown that they play a fundamental role in the recombination. Finally, from the analysis of the time-resolved correlations at different excitation intensities, we confirmed the contribution to the luminescence of transitions involving different valence subbands.
    Journal of Luminescence 01/1996; 68(2). · 2.14 Impact Factor
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    ABSTRACT: To detect mRNA expression of nitric oxide synthase (NOS) isoforms in human monocytes/macrophages reverse transcription polymerase chain reaction (RT-PCR) was used. mRNA was isolated from stimulated or unstimulated monocytes/macrophages and RT-PCR was performed using oligonucleotide primers derived from mRNA sequences of either human endothelial constitutive (c) or human hepatocyte inducible (i) NOS. RT-PCR of mRNA isolated from resting monocytes and macrophages resulted in the amplification of a cNOS specific mRNA fragment. When the cells were stimulated with lipopolysaccharide (LPS)/interferon-γ (IFN-γ) prior to mRNA extraction, RT-PCR yielded an iNOS-specific amplification product. Whereas the activation of both cell types was accompanied by expression of iNOS mRNA, the cNOS signal seemed to be diminished upon immunostimulation. Not only in purified human monocytes but also in the human monocytoid cell lines MonoMac 6, THP-1, and U937 cNOS mRNA was detected. The data clearly demonstrate the presence of iNOS and cNOS mRNA in human monocytes/macrophages and provide the necessary tools to investigate the regulation of NO synthesis in these cell populations.
    European Journal of Immunology 07/1994; 24(8):1941 - 1944. · 4.97 Impact Factor