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Query: UNIPROT:P06889 (Mol)
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We have previously reported on the cloning and bacterial expression of a biologically active scFv antibody fragment (scFv-D9D10) derived from the mouse anti-human interferon-gamma (HuIFN-gamma) antibody, D9D10. Since the variable (V) regions were isolated by means of VH and VL consensus sequence-specific PCR primers and cloned in an expression vector relying on primer-incorporated restriction sites, some amino acids (aa) at the N- and C-terminal ends of the cloned V domains were expected to differ from the corresponding ones in the natural D9D10 antibody. Therefore, the naturally occurring sequences of both V domains were isolated by means of traditional cDNA synthesis procedures. In comparison with scFv-D9D10, the "natural" V sequences differed in three aa in VH and three in VL. The V domains of scFv-D9D10 were adapted to their natural sequence by means of PCR-directed mutagenesis to yield scFv-D9D10N. Comparison of the binding and neutralizing potentials of both antibody fragments did not reveal differences in either of both activities. In addition, their affinities for HuIFN-gamma were found to be equal. These results show that murine VH and VL consensus-specific primers can yield antibody fragments having functional properties equivalent to those of the natural scFv. Information on the impact of the use of V-specific primers on kinetics of interaction between the recombinant antibody and the corresponding antigen is important for the development of most engineered antibodies or their fragments.
Mol Immunol 1995 May
PMID:Effect of VH and VL consensus sequence-specific primers on the binding and neutralizing potential of a single-chain FV directed towards HuIFN-gamma. 778 54

We have studied the production of nitric oxide (NO) and superoxide by murine peritoneal macrophages during activation. The production of NO was induced by activation of cells with recombinant interferon-gamma (rIFN-gamma) and lipopolysaccharide (LPS). Phorbol 12-myristate 13-acetate (PMA)-induced formation of superoxide also increased during activation. However, NO released by the activated macrophages exerted the inhibitory effect on the superoxide formation in the same cells. This fact is supported by the increased production of superoxide when the cells were treated with NG-monomethyl-L-arginine (NGMMA) in addition to stimulation with rIFN-gamma and LPS. The production of superoxide was also inhibited by treatment with sodium nitroprusside (SPN), which spontaneously released nitric oxide in vitro, and at the same time there was increased adenosine diphosphate (ADP)-ribosylation of 37 kDa proteins of the cytoplasm. The 3-aminobenzamide (3-AB) treatment, which decreased ADP-ribosylation, partially reversed SNP-induced inhibition of superoxide generation in macrophages. The above data provide evidence that NO decreases superoxide formation possibly via ADP-ribosylation.
Biochem Mol Biol Int 1994 Aug
PMID:Generation of nitric oxide inhibits formation of superoxide in macrophages during activation. 784 11

Early experience with recombinant adenoviruses for gene transfer to airway epithelium suggests that these vectors are associated with the development of inflammation. The mechanisms for this are unclear, but previous work has shown that respiratory viruses can cause increased expression of intercellular adhesion molecule-1 (ICAM-1) on airway epithelial cells. We therefore hypothesized that recombinant adenoviruses may induce ICAM-1 expression and thereby facilitate the development of airway inflammation. To address this, primary cultures of human bronchial epithelial cells were examined for ICAM-1 expression by flow cytometry after infection with a serotype 5, E1/E3-deleted recombinant adenovirus containing the Escherichia coli LacZ reporter gene driven by the cytomegalovirus promoter (Ad.CMVlacZ). Compared with control cells, ICAM-1 expression was unchanged after infection with Ad.CMVlacZ, but increased after infection with wild-type adenovirus. Treatment of Ad.CMVlacZ-infected cells with interferon-gamma (IFN) resulted in increased ICAM-1 expression, but to a lower level than that seen in cells treated with IFN alone, indicating that recombinant adenovirus infection blunted IFN-induced up-regulation of ICAM-1. Adhesion of human leukocytes to human bronchial epithelial cells was not increased after Ad.CMVlacZ infection, thereby excluding an ICAM-1-independent increase in leukocyte-epithelial adhesion. The results for ICAM-1 expression were confirmed in vivo, as immunostaining of human bronchial xenografts infected with Ad.CMVlacZ revealed basilar epithelial staining with ICAM-1, but no increased expression on cells expressing beta-galactosidase. This study demonstrates that unlike other respiratory viruses, recombinant E1/E3-deleted adenovirus does not cause increased ICAM-1 expression on human bronchial epithelium in vitro or in vivo nor increased leukocyte adhesion in vitro.
Am J Respir Cell Mol Biol 1995 Feb
PMID:ICAM-1 expression on bronchial epithelium after recombinant adenovirus infection. 786 13

Lower respiratory tract exposure to high oxygen (O2) concentrations is known to induce changes in pulmonary function through effects on several cell types located within the lung parenchyma, including pulmonary macrophages (PM). We studied the effects of hyperoxic exposure on phagocytosis via Fc-gamma receptors (FcR) on isolated murine PM. PM cultured in hyperoxic conditions exhibited little change in ingestion via FcR for up to 96 h, compared with significant increases in ingestion by PM cultured in 21% O2 over the same time period. This suppression was reversible and occurred whether 50 or 100% O2 concentrations were used for hyperoxic exposure. Addition of the potent macrophage-activating agent interferon-gamma (IFN-gamma) to cultured PM further increased FcR-mediated phagocytosis in normoxic PM but had no effect on PM cultured in 100% O2. Analysis of FcR expression by flow cytometry using monoclonal antibodies specific for two different FcR classes revealed that culture in normoxic conditions increased surface expression of both FcR classes. Hyperoxic culture inhibited up-regulation of the high-affinity FcR but did not affect low-affinity FcR up-regulation, suggesting that hyperoxic effects were not due solely to effects on regulation of FcR expression. However, hyperoxic exposure completely suppressed FcR-mediated actin polymerization. These findings suggest that hyperoxic exposure impairs PM ability to increase FcR-mediated phagocytic activity after appropriate stimulation, which could impair the lung's defenses against infection.
Am J Respir Cell Mol Biol 1995 Feb
PMID:Hyperoxic suppression of Fc-gamma receptor-mediated phagocytosis by isolated murine pulmonary macrophages. 786 16

The Clara cell 16 kD protein (CC16), the predominant product of the Clara cells lining the bronchiolar epithelium, is thought to protect the respiratory and urogenital tract from unwanted inflammatory reactions through its immunosuppressive action. In this report, we show evidence that CC16 establishes an anti-inflammatory activity by interfering with the interferon-gamma (IFN-gamma)-mediated actions of the cytokine network. The HuIFN-gamma production of stimulated single-donor peripheral blood mononuclear cells is inhibited by the presence of doses of CC16 in the range of 10(-12) M, with a maximal inhibition (up to 95%) when interleukin-2 is used as a stimulating agent. CC16 also diminishes the biologic activity of IFN-gamma: both the antiviral activity and the stimulation of phagocytosis by IFN-gamma, measured by means of chemiluminescence, are reduced in the presence of CC16. These observations indicate that CC16 acts as an anticytokine and could give new insight in the potential role of the Clara cells.
Am J Respir Cell Mol Biol 1995 Feb
PMID:Potent inhibition of both human interferon-gamma production and biologic activity by the Clara cell protein CC16. 786 18

We have recently shown that interferon-gamma (IFN-gamma) stimulated immunocytochemical staining of the intercellular adhesion molecule ICAM-1 may be dependent on inositol phosphate formation in the human renal carcinoma cell line CaKi-1. In the present study we investigated the possible role of GTP-binding proteins (G-proteins) during IFN-gamma signalling. Preincubation of CaKi-1 cells for 24 h with increasing amounts of pertussis toxin (PT) or cholera toxin (CT), two regulators of G-protein activity, inhibited IFN-gamma induced ICAM-1 staining. Preincubation with PT or CT for 24 h also inhibited IFN-gamma induced inositol 1-monophosphate (Ins 1-P), inositol 1,4 bisphosphate (Ins 1,4-P2) and inositol 1,4,5 trisphosphate (Ins 1,4,5-P3) formation. Our findings suggest that IFN-gamma induced ICAM-1 staining and inositol phosphate formation in CaKi-1 cells is dependent on a PT and CT sensitive signalling pathway. This may reflect a role for G-proteins in the coupling of IFN-gamma receptor activation and phospholipase C catalyzed phosphoinositide hydrolysis.
Virchows Arch B Cell Pathol Incl Mol Pathol 1993
PMID:Effects of pertussis and cholera toxin on the interferon-gamma stimulated immunocytochemical staining of ICAM-1 and inositol phosphate formation in a human renal carcinoma cell line. 790 88

1. Interleukin-10 (IL-10) has a wide range of activities in the immune system such as modulation of interferon-gamma (IFN-gamma) and antibody production. The neuropeptide hormone corticotropin (ACTH) has similar activities, suggesting that a bidirectional communication mechanism operates between the immune and the neuroendocrine system involving these two substances. 2. Murine pituitary tumor cells (AtT-20) were found to produce up to 3 ng/ml of IL-10. 3. Pituitary cell corticotropin production was enhanced by IL-10 treatment. 4. IL-10 induced the production of ACTH in mouse splenocytes. 5. Authenticity of pituitary-derived IL-10 was shown by the demonstration of identical nucleic acid sequences of reverse-transcribed, polymerase chain reaction amplified fragments of cDNA obtained from murine splenocytes, a murine pituitary tumor cell line, and freshly isolated murine pituitaries.
Cell Mol Neurobiol 1994 Feb
PMID:Evidence for the production and action of interleukin-10 in pituitary cells. 795 60

Perhaps as many as 25-50% of adult patients and children with acquired immunodeficiency syndrome (AIDS) eventually suffer from neurological manifestations, including dysfunction of cognition, movement, and sensation. How can human immunodeficiency virus type 1 (HIV-1) result in neuronal damage if neurons themselves are for all intents and purposes not infected by the virus? This article reviews a series of experiments leading to a hypothesis that accounts at least in part for the neurotoxicity observed in the brains of AIDS patients. There is growing support for the existence of HIV- or immune-related toxins that lead indirectly to the injury or demise of neurons via a potentially complex web of interactions among macrophages (or microglia), astrocytes, and neurons. HIV-infected monocytoid cells (macrophages, microglia, or monocytes), after interacting with astrocytes, secrete eicosanoids, i.e., arachidonic acid and its metabolites, including platelet-activating factor. Macrophages activated by HIV-1 envelope protein gp120 also appear to release arachidonic acid and its metabolites. In addition, interferon-gamma (IFN-gamma) stimulation of macrophages induces release of the glutamate-like agonist, quinolinate. Furthermore, HIV-infected macrophage production of cytokines, including TNF-alpha and IL1-beta, contributes to astrogliosis. A final common pathway for neuronal susceptibility appears to be operative, similar to that observed in stroke, trauma, epilepsy, neuropathic pain, and several neurodegenerative diseases, possibly including Huntington's disease, Parkinson's disease, and amyotrophic lateral sclerosis. This mechanism involves the activation of voltage-dependent Ca2+ channels and N-methyl-D-aspartate (NMDA) receptor-operated channels, and, therefore, offers hope for future pharmacological intervention. This article focuses on clinically tolerated calcium channel antagonists and NMDA antagonists with the potential for trials in humans with AIDS dementia in the near future.
Mol Neurobiol
PMID:HIV-related neuronal injury. Potential therapeutic intervention with calcium channel antagonists and NMDA antagonists. 799 15

The ribosome binding site (RBS) of prokaryotic mRNA is divided into 5' and 3' portions by the translation initiation codon. Although it is well known that the presence of an appropriate RBS containing only the 5' portion is sufficient to direct the initiation of protein synthesis, the 3' portion appears to play a significant role in modulating the initiation process as well. Here we examine the influence of adenine-rich motifs frequently found in the 3' portion of highly expressed prokaryotic mRNAs. Two synthetic DNA fragments, GAGAAAAAAATC (corresponding to the first 12 nucleotides following the initiation codon of the chloramphenicol acetyltransferase gene), and AAAAAAATTAA were used to modify the beginning of the coding region of the human immune interferon-gamma (IFN-gamma) gene. The level of the protein synthesis in Escherichia coli directed by plasmids containing these constructs was quantitated. We found that placing either adenine-rich motif in the 3' portion of the RBS strongly enhanced gene expression, probably through an effect on translation initiation. We have also compared the protein expression levels of these gene constructs containing different series of 5'-RBSs with varying precistronic lengths and Shine-Dalgarno sequence lengths. The results suggest a positive functional role for the 3' adenine-rich motif. A possible mechanism for these effects is discussed.
J Mol Biol 1994 Jul 01
PMID:The influence of adenine-rich motifs in the 3' portion of the ribosome binding site on human IFN-gamma gene expression in Escherichia coli. 802 37

The present study examines interferon-gamma (IFN gamma)-induced changes in the expression of immunomodulatory genes, proliferation-associated genes, and squamous-specific genes in primary cultures of human bronchial epithelial cells and fibroblasts. IFN gamma induced the expression of guanylate binding protein (GBP or p67) and the MHC class II antigen, HLADR alpha, in both epithelial cells and fibroblasts. In contrast, the expression of complement component C3 was induced in bronchial epithelial cells but not in fibroblasts. Similarly, IFN gamma induced growth arrest (EC50 approximately 50 U/ml) only in bronchial epithelial cells. This growth arrest was accompanied by a down-regulation of cdc2, E2F-1, and p53 mRNA levels and was associated with expression of the squamous-specific marker genes, transglutaminase type I and cornifin. These findings are consistent with IFN gamma inducing squamous differentiation in bronchial epithelial cells. In contrast, several lung carcinoma cell lines did not respond to IFN gamma with respect to the down-regulation of proliferation-associated genes or the induction of squamous-specific genes. However, GBP expression was induced in all the cell lines in response to IFN gamma. The present study demonstrates that cultured human bronchial epithelial cells are sensitive to the immunomodulatory, growth-inhibitory, and differentiation-inducing properties of IFN gamma. In contrast, several lung carcinoma cell lines are insensitive to the growth-inhibitory and differentiation-inducing actions of IFN gamma, suggesting they may have acquired defects in certain IFN gamma signaling pathways. Although the growth of human bronchial fibroblasts is not altered, expression of certain immunomodulatory genes is induced by IFN gamma.(ABSTRACT TRUNCATED AT 250 WORDS)
Am J Respir Cell Mol Biol 1994 Aug
PMID:Differential responsiveness of human bronchial epithelial cells, lung carcinoma cells, and bronchial fibroblasts to interferon-gamma in vitro. 804 75


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