Interferon-alpha acts at the preoptic hypothalamus to reduce natural killer cytotoxicity in rats

1995 ◽  
Vol 268 (6) ◽  
pp. R1406-R1410 ◽  
Author(s):  
S. Take ◽  
D. Uchimura ◽  
Y. Kanemitsu ◽  
T. Katafuchi ◽  
T. Hori
Keyword(s):  
Natural Killer ◽  
Interferon Alpha ◽  
Ventromedial Hypothalamus ◽  
Human Interferon ◽  
Nk Activity ◽  
Ifn Alpha ◽  
Rats And Mice ◽  
The Brain ◽  
Natural Killer Cytotoxicity ◽  
Sympathetic Pathway

We previously demonstrated that an intracerebroventricular injection of recombinant human interferon-alpha (rhIFN-alpha) reduced the cytotoxicity of splenic natural killer (NK) cells in rats and mice. In the present study, we investigated the brain sites at which rhIFN-alpha acts to suppress splenic NK activity in unanesthetized rats implanted unilaterally with a chronic hypothalamic cannula. A microinjection of 200 U of rhIFN-alpha into the medial part of the preoptic hypothalamus reduced NK activity to approximately 60% of control 30 min after the injection. Administration of 50 U of rhIFN-alpha also decreased NK activity to approximately 80%. The injection of 200 U of rhIFN-alpha into other hypothalamic areas (lateral preoptic hypothalamus, ventromedial hypothalamus, lateral hypothalamus, and paraventricular nucleus) had no effect. The medial preoptic hypothalamus-rhIFN-alpha-induced immunosuppression was completely blocked by splenic denervation, but not by adrenalectomy. These results suggest that IFN-alpha suppresses splenic NK activity predominantly through the medial preoptic hypothalamus-sympathetic pathway.

Central interferon-alpha inhibits natural killer cytotoxicity through sympathetic innervation

1993 ◽  
Vol 265 (2) ◽  
pp. R453-R459 ◽  
Author(s):  
S. Take ◽  
T. Mori ◽  
T. Katafuchi ◽  
T. Hori
Keyword(s):  
Natural Killer ◽  
Interferon Alpha ◽  
Viral Infections ◽  
Sympathetic Innervation ◽  
Nk Activity ◽  
Ifn Alpha ◽  
Nk Cytotoxicity ◽  
The Brain ◽  
Natural Killer Cytotoxicity ◽  
Crf System

The brain has been known to produce high levels of interferon-alpha (IFN-alpha) during viral infections. We investigated the central and peripheral mechanisms of the brain IFN-alpha-induced suppression of natural killer (NK) cytotoxicity in the rat. The activity of NK cells in the spleen and the peripheral blood decreased 30-120 min after intracerebroventricular (icv) injection of recombinant human IFN-alpha of > 1,000 U but not after its intraperitoneal injection. This effect was antagonized by pretreatment with icv naltrexone (NLTX). Splenic denervation was observed to completely abolish the IFN-alpha-induced suppression of NK activity, whereas bilateral adrenalectomy did not. Furthermore, this immunosuppression was blocked by an icv injection of an antagonist of corticotropin-releasing factor (CRF), alpha-helical CRF-(9-41). The icv injection of CRF resulted in reduced NK activity, which was not affected by NLTX. The results suggest that brain IFN-alpha activates the CRF system through central opioid receptors and thereby suppresses the NK cytotoxicity predominantly through splenic sympathetic innervation.

Two distinct families of human and bovine interferon-alpha genes are coordinately expressed and encode functional polypeptides

1985 ◽  
Vol 5 (4) ◽  
pp. 768-779
Author(s):  
D J Capon ◽  
H M Shepard ◽  
D V Goeddel
Keyword(s):  
Amino Acid ◽  
Interferon Alpha ◽  
Cdna Probe ◽  
Class Ii ◽  
Class I ◽  
Human Interferon ◽  
Amino Acid Sequence Homology ◽  
Ifn Alpha ◽  
Extensive Analysis ◽  
Alpha Gene

The classical human interferon-alpha (HuIFN-alpha) gene family is estimated to consist of 15 or more nonallelic members which encode proteins sharing greater than 77% amino acid sequence homology. Low-stringency hybridization with a HuIFN-alpha cDNA probe permitted the isolation of two distinct classes of bovine IFN-alpha genes. The first subfamily (class I) is more closely related to the known HuIFN-alpha genes than to the second subfamily (class II) of bovine IFN-alpha genes. Extensive analysis of the human genome has revealed a HuIFN-alpha gene subfamily corresponding to the class II bovine IFN-alpha genes. The class I human and bovine IFN-alpha genes encode mature IFN polypeptides of 165 to 166 amino acids, whereas the class II IFN-alpha genes encode 172 amino acid proteins. Expression in Escherichia coli of members of both gene subfamilies results in polypeptides having potent antiviral activity. In contrast to previous studies which found no evidence of class II IFN-alpha protein or mRNA expression, we demonstrate that the class I and class II IFN-alpha genes are coordinately induced in response to viral infection.

scholarly journals Human recombinant interferon alpha-2C enhances the expression of class II HLA antigens on hairy cells

Blood ◽  
1986 ◽  
Vol 67 (2) ◽  
pp. 458-464 ◽  
Author(s):  
L Baldini ◽  
A Cortelezzi ◽  
N Polli ◽  
A Neri ◽  
L Nobili ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Interferon Alpha ◽  
Hla Antigens ◽  
Class Ii ◽  
Human Interferon ◽  
Experimental Conditions ◽  
Recombinant Interferon ◽  
Ifn Alpha ◽  
Stimulatory Capacity ◽  
Hairy Cells

Abstract Isolated splenic hairy cells from three untreated patients were cultured in presence of recombinant human interferon alpha-2C (IFN alpha). Ultrastructural cytochemistry and immunophenotype analysis with a large panel of monoclonal antibodies were performed to study cellular modification induced by IFN alpha. Hairy cells showed a typical pheno- type: Smlg+, B1+, BA1+/-, anti-Tac+, OKDR+, Leu-M5+, HC2+, TRAP+, myeloperoxidase-. Under our experimental conditions, we found no direct cytotoxic effects or significant variations in morphology, cytochemistry, and percentage of reactivity with the tested monoclonal antibodies. After culturing in the presence of different doses of IFN alpha, we observed a significant enhancement of the expression of class II HLA antigens as demonstrated by increased fluorescence for OKDR, OKla, Leu-10 at fluorescence-activated cell sorting analysis. In agreement with this finding IFN alpha-treated hairy cells showed an increased stimulatory capacity v allogeneic T cells in one-way mixed lymphocyte reaction. To our knowledge this is the first report describing the induction of class II HLA antigens on hairy cells by IFN alpha.

scholarly journals Natural killer cell activity from hemophiliacs exhibits differential responses to various forms of interferon

Blood ◽  
1986 ◽  
Vol 67 (1) ◽  
pp. 164-167 ◽  
Author(s):  
DS Matheson ◽  
BJ Green ◽  
MC Poon ◽  
MJ Fritzler ◽  
DI Hoar ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Killer Cell ◽  
Cell Activity ◽  
Clotting Factor ◽  
Foreign Protein ◽  
Nk Activity ◽  
Ifn Gamma ◽  
Antigen Stimulation ◽  
Ifn Alpha

Abstract Patients with hemophilia are at risk for the development of acquired immunodeficiency syndrome (AIDS). Patients with AIDS have recurrent infections and/or malignancy and altered immune response, including decreased T lymphocyte counts, decreased T helper lymphocytes, defective T cell blastogenesis, hypergammaglobulinemia, defective natural killer (NK) activity and impaired response of NK to interferon- beta (IFN-beta). It is feasible that chronic antigen stimulation with subsequent release of interferon could be related to the impaired NK reactivity to IFN-beta of patients with AIDS. Because hemophiliacs are subjected to chronic antigen stimulation secondary to the administration of foreign protein, the reactivity of NK cells from patients with hemophilia to IFN-alpha, IFN-beta and IFN-gamma was studied. Eight patients with hemophilia requiring high levels of clotting factor replacement were assessed. Three patients were antibody positive to HTLV-III. All had normal baseline NK cell function. In the first set of experiments, all patients responded normally to in vitro IFN-alpha by increasing NK activity, but four patients had significant failure and two had mild impairment in NK response to IFN-beta. This latter observation was particularly evident at very low concentrations of IFN. In repeated experiments, seven of eight had impaired NK response to IFN-beta and IFN-gamma but normal response to IFN-alpha. Only one patient's NK cells responded better to IFN-gamma. There was no obvious correlation of these findings to antibody status to HTLV-III. Chronic antigen stimulation and the modulation of interferon receptors are discussed as possible mechanisms that could produce these findings.

scholarly journals Natural killer cell activity from hemophiliacs exhibits differential responses to various forms of interferon

Blood ◽  
1986 ◽  
Vol 67 (1) ◽  
pp. 164-167
Author(s):  
DS Matheson ◽  
BJ Green ◽  
MC Poon ◽  
MJ Fritzler ◽  
DI Hoar ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Killer Cell ◽  
Cell Activity ◽  
Clotting Factor ◽  
Foreign Protein ◽  
Nk Activity ◽  
Ifn Gamma ◽  
Antigen Stimulation ◽  
Ifn Alpha

Patients with hemophilia are at risk for the development of acquired immunodeficiency syndrome (AIDS). Patients with AIDS have recurrent infections and/or malignancy and altered immune response, including decreased T lymphocyte counts, decreased T helper lymphocytes, defective T cell blastogenesis, hypergammaglobulinemia, defective natural killer (NK) activity and impaired response of NK to interferon- beta (IFN-beta). It is feasible that chronic antigen stimulation with subsequent release of interferon could be related to the impaired NK reactivity to IFN-beta of patients with AIDS. Because hemophiliacs are subjected to chronic antigen stimulation secondary to the administration of foreign protein, the reactivity of NK cells from patients with hemophilia to IFN-alpha, IFN-beta and IFN-gamma was studied. Eight patients with hemophilia requiring high levels of clotting factor replacement were assessed. Three patients were antibody positive to HTLV-III. All had normal baseline NK cell function. In the first set of experiments, all patients responded normally to in vitro IFN-alpha by increasing NK activity, but four patients had significant failure and two had mild impairment in NK response to IFN-beta. This latter observation was particularly evident at very low concentrations of IFN. In repeated experiments, seven of eight had impaired NK response to IFN-beta and IFN-gamma but normal response to IFN-alpha. Only one patient's NK cells responded better to IFN-gamma. There was no obvious correlation of these findings to antibody status to HTLV-III. Chronic antigen stimulation and the modulation of interferon receptors are discussed as possible mechanisms that could produce these findings.

scholarly journals Positive self regulation of cytotoxicity in human natural killer cells by production of interferon upon exposure to influenza and herpes viruses.

1982 ◽  
Vol 156 (4) ◽  
pp. 1222-1234 ◽  
Author(s):  
J Y Djeu ◽  
N Stocks ◽  
K Zoon ◽  
G J Stanton ◽  
T Timonen ◽  
...  
Keyword(s):  
T Cells ◽  
Natural Killer ◽  
Influenza A ◽  
Nk Cell ◽  
Self Regulation ◽  
Cell Types ◽  
Nk Activity ◽  
Ifn Alpha ◽  
Lytic Function ◽  
Human Natural Killer Cells

Augmentation of natural killer (NK) activity by influenza A/PC and HSV-1 viruses appears to be caused by the induction of interferon (IFN) within the NK cell population itself. These viruses induced high levels of IFN production by human large granular lymphocytes (LGL) that could be readily isolated from peripheral blood by Percoll density gradients. These LGL, which have been previously shown to account for and to be highly associated with endogenous NK activity, became augmented in their lytic function during the 18-h period that IFN was induced. Non-LGL helper cells did not appear to be required in the NK-IFN system (either T cells, B cells, or monocytes). Removal of these latter cell types by treatment with OKT3 plus complement, anti-IgM plus complement, or preincubation with silica or carrageenan had no effect on the ability of LGL to respond to the viruses. Production of IFN was also detected, albeit at lower levels, from monocytes cultured for 18 h with viruses, but no cytotoxic activity was induced. On the other hand, T cells, even in the presence of monocytes, showed neither property, and longer cultures, with virus up to 4 d, still did not alter the pattern. The IFN produced by both LGL and monocytes were predominantly IFN-alpha, as assessed by neutralization assays with antisera to IFN-alpha, -beta, and -gamma. In an individual with detectable serum antibodies to influenza A/PC, however, the IFN induced in LGL appeared to be gamma, presumably because of specific recognition of the virus. These data suggest an efficient positive self-regulatory mechanism in NK cells that may be readily switched on by viruses.

scholarly journals Human recombinant interferon alpha-2C enhances the expression of class II HLA antigens on hairy cells

Blood ◽  
1986 ◽  
Vol 67 (2) ◽  
pp. 458-464 ◽  
Author(s):  
L Baldini ◽  
A Cortelezzi ◽  
N Polli ◽  
A Neri ◽  
L Nobili ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Interferon Alpha ◽  
Hla Antigens ◽  
Class Ii ◽  
Human Interferon ◽  
Experimental Conditions ◽  
Recombinant Interferon ◽  
Ifn Alpha ◽  
Stimulatory Capacity ◽  
Hairy Cells

Isolated splenic hairy cells from three untreated patients were cultured in presence of recombinant human interferon alpha-2C (IFN alpha). Ultrastructural cytochemistry and immunophenotype analysis with a large panel of monoclonal antibodies were performed to study cellular modification induced by IFN alpha. Hairy cells showed a typical pheno- type: Smlg+, B1+, BA1+/-, anti-Tac+, OKDR+, Leu-M5+, HC2+, TRAP+, myeloperoxidase-. Under our experimental conditions, we found no direct cytotoxic effects or significant variations in morphology, cytochemistry, and percentage of reactivity with the tested monoclonal antibodies. After culturing in the presence of different doses of IFN alpha, we observed a significant enhancement of the expression of class II HLA antigens as demonstrated by increased fluorescence for OKDR, OKla, Leu-10 at fluorescence-activated cell sorting analysis. In agreement with this finding IFN alpha-treated hairy cells showed an increased stimulatory capacity v allogeneic T cells in one-way mixed lymphocyte reaction. To our knowledge this is the first report describing the induction of class II HLA antigens on hairy cells by IFN alpha.

scholarly journals Two distinct families of human and bovine interferon-alpha genes are coordinately expressed and encode functional polypeptides.

1985 ◽  
Vol 5 (4) ◽  
pp. 768-779 ◽  
Author(s):  
D J Capon ◽  
H M Shepard ◽  
D V Goeddel
Keyword(s):  
Amino Acid ◽  
Interferon Alpha ◽  
Cdna Probe ◽  
Class Ii ◽  
Class I ◽  
Human Interferon ◽  
Amino Acid Sequence Homology ◽  
Ifn Alpha ◽  
Extensive Analysis ◽  
Alpha Gene

The classical human interferon-alpha (HuIFN-alpha) gene family is estimated to consist of 15 or more nonallelic members which encode proteins sharing greater than 77% amino acid sequence homology. Low-stringency hybridization with a HuIFN-alpha cDNA probe permitted the isolation of two distinct classes of bovine IFN-alpha genes. The first subfamily (class I) is more closely related to the known HuIFN-alpha genes than to the second subfamily (class II) of bovine IFN-alpha genes. Extensive analysis of the human genome has revealed a HuIFN-alpha gene subfamily corresponding to the class II bovine IFN-alpha genes. The class I human and bovine IFN-alpha genes encode mature IFN polypeptides of 165 to 166 amino acids, whereas the class II IFN-alpha genes encode 172 amino acid proteins. Expression in Escherichia coli of members of both gene subfamilies results in polypeptides having potent antiviral activity. In contrast to previous studies which found no evidence of class II IFN-alpha protein or mRNA expression, we demonstrate that the class I and class II IFN-alpha genes are coordinately induced in response to viral infection.

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