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IFN-alpha

interferon-alpha, abbr. also aIFN.


ALTERNATIVE NAMES

B-cell interferon;
Buffy coat interferon;
Foreign cell induced interferon;
Leukocyte interferon (LeIFN);
Lymphoblast interferon (LyIFN-alpha);
Lymphoblastoid interferon (LyIFN-alpha); abbr. frequently HLBI [human lymphoblastoid interferon]
Namalwa interferon; see also: Namalwa cell line
pH2-stable interferon;
Type 1 interferon;
RSV induced factor.
Some of the activity ascribed to EP (endogenous pyrogens) can be attributed also to IFN-alpha. See also: individual entries for further information.

Preparations of leukocyte interferon and lymphoblastoid interferon are mixtures of relatively undefined composition of various IFN-alpha subtypes. LeIFN-alpha may contain further factors that influence the proliferation and differentiation of cells (see also: Cytokines) while LyIFN-alpha may contain variable amounts of IFN-beta. For a synthetic IFN-alpha see also: Consensus interferon.


SOURCES

IFN-alpha forms are produced by monocytes/macrophages, lymphoblastoid cells, fibroblasts, and a number of different cell types following induction by viruses, nucleic acids, glucocorticoid hormones, and low-molecular weight substances (n-butyrate, 5-bromodeoxy uridine).


PROTEIN CHARACTERISTICS

At least 23 different variants of IFN-alpha are known. The individual proteins have molecular masses between 19-26 kDa and consist of proteins with lengths of 156-166 and 172 amino acids.

All IFN-alpha subtypes possess a common conserved sequence region between amino acid positions 115-151 while the amino-terminal ends are variable. Many IFN-alpha subtypes differ in their sequences at only one or two positions. Naturally occurring variants also include proteins truncated by 10 amino acids at the carboxy-terminal end.

Disulfide bonds are formed between cysteines at positions 1/98 and 29/138. The disulfide bond 29/138 is essential for biological activity while the 1/98 bond can be reduces without affecting biological activity. All IFN-alpha forms contain a potential glycosylation site but most subtypes are not glycosylated. In contrast to IFN-gamma IFN-alpha proteins are stable at pH2.


GENE STRUCTURE

There are at least 23 different IFN-alpha genes. They have a length of 1-2 kb and are clustered on human chromosome 9p22. It is not known whether all these genes are expressed following stimulation of the cells. In some cell systems expression of some subtypes (IFN-alpha-1, IFN-alpha-2, IFN-alpha-4) is stronger than those of others. IFN-alpha genes do not contain intron sequences found in many other eukaryotic genes (see also: gene expression).

Based upon the structures two types of IFN-alpha genes, designated class 1 and II, are distinguished. They encode proteins of 156-166 and 172 amino acids, respectively.

Deletions covering 9p22 are observed frequently in cells of lymphoblastoid leukemias. It is not known to date whether this is of significance with respect to interferon expression.


RECEPTORS

For further information see: IFNAR1 and IFNAR2. The gene encoding the IFN-alpha receptor maps to human chromosome 21q22.1. IFN-alpha and IFN-beta are thought to bind to the same IFN binding subunit which is expressed in 100-5000 copies in IFN-alpha sensitive and -resistant cells and is associated with other proteins. The interferon IFN-omega and also some other Type 1 interferons bind to the IFN-alpha/IFN-beta receptor. Another receptor expressed on B-lymphocytes is identical with CD21. This receptor also binds Epstein-Barr virus through its gp350/220 coat protein.

Signal transduction mechanisms elicited after binding of IFN-alpha to its receptors involves tyrosine phosphorylation (see also: PTK; protein tyrosine kinase) of various non-receptor tyrosine kinases belonging to the Janus kinases.

Soluble forms of the IFN-alpha receptor, corresponding to truncated forms of the extracellular domain of the cell surface IFN-alpha receptor, have been found in human serum and in normal human urine.


BIOLOGICAL ACTIVITIES

All known subtypes of IFN-alpha show the same antiviral antiparasitic, antiproliferative activities in suitable bioassays although they may differ in relative activities.

Human IFN-alpha is also a potent antiviral substance in murine, porcine, and bovine cell systems. Human IFN-alpha is less active in rodent cells. Site-directed mutagenesis techniques have been used to create some variants of certain subtypes (IFN-alpha-2) that display approximately 100-fold enhanced antiviral activities in mouse cells.

IFN-alpha inhibits the expression of a number of cytokines in hematopoietic progenitor cells (see: hematopoiesis) that in turn induce a state of competence in these cells allowing them to pass from the G0 into the S phase of the cell cycle.

The growth of some tumor cell types in vitro is inhibited by IFN-alpha which may stimulate also the synthesis of tumor-associated cell surface antigens. In renal carcinomas IFN-alpha reduces the expression of receptors for EGF. IFN-alpha also inhibits the growth of fibroblasts and monocytes in vitro. IFN-alpha also inhibits the proliferation of B-cell in vitro and blocks the synthesis of antibodies. IFN-alpha also selectively blocks the expression of some mitochondrial genes.

IFN-alpha specifically induces the expression of a number of genes (see also: Mx). These genes contain regulatory DNA sequences within their promoter regions (ISRE; Interferon-stimulated response element; see: IRS, interferon response sequence) that function as binding sites for a number of transcription factors. Some of these genes are expressed also in response to other interferons (see: IFN).

The occurrence of spontaneous antibodies directed against IFN-alpha has been observed in patients with certain types of autoimmune diseases, generalized virus infections, and a number of tumors. Some inbred strains of mice appear to produce constitutively antibodies directed against IFN-alpha or IFN-beta.


TRANSGENIC ANIMALS, KNOCK-OUT, AND ANTISENSE STUDIES

Interferon expression in the testes of transgenic mice has been shown to cause sterility.


DETECTION AND ASSAY METHODS

IFN-alpha is assayed by a cytopathic effect reduction test employing human and bovine cell lines (see: MDBK, WISH). Minute amounts of IFN-alpha can be assayed also by detection of the Mx protein specifically induced by this interferon. A sandwich ELISA employing bispecific monoclonal antibodies for rapid detection (10 units/mL = 0.1 ng/mL within 2-3 hours) is available. Lewis describes a bioassay based on induction of a reporter gene linked to a promoter element that responds to interferons (see: IFN). Production of the reporter gene product is dose-dependent in the range of 1 to approximately 100 U/mL of IFN and sensitivity is comparable to standard cytopathic effect assays.

The MxR assay (see: Mx) involves use of a genetically engineered Vero cell line to measure IFN-alpha.

Mire-Sluis et al (1996) have described bioassays for IFN-alpha, IFN-beta and IFN-omega that exploit the ability of these factors to inhibit proliferation of TF-1 cells induced by GM-CSF. The bioassays can be used also with Epo and TF-1 cells, or Epo and Epo-transfected UT-7 cells.

For further information see also subentry "Assays" in the reference section. For further information on assays for cytokines see also: bioassays, cytokine assays.


CLINICAL USE AND SIGNIFICANCE

IFN-alpha is mainly employed as a standard therapy for hairy cell leukemia, metastasizing renal carcinoma and AIDS-associated angiogenic tumors of mixed cellularity known as Kaposi sarcomas. It is also active against a number of other tumors and viral infections. IFN-alpha is approved by the Food and Drug Administration for the treatment of condyloma acuminata (genital or venereal warts).

Hairy cell leukemia constitutes approximately 2 % of all leukemias. Treatment with IFN-alpha markedly improves blood and bone marrow parameters. The number of necessary blood transfusions is reduced and the frequency of life-threatening infections is also reduced.

Treatment of disseminated Kaposi sarcomas results in complete or partial remissions in approximately 30-40 % of the patients. In patients with advanced malignant melanomas treatment with a combination of IFN-alpha and chemotherapy (Dacarbazin, DTIC) has been found to be particularly effective and to be superior to treatment with IFN-alpha alone. Complete remissions and also a significant increase in survival times have been observed in responders. Intralesional therapy with IFN-alpha has been found to cause almost complete disappearance of tumors in 80 % of patients with basaliomas.

Moderate and high doses of IFN-alpha are one of the most effective forms of treatment of metastasizing renal carcinomas. Response rates of combinations of vinblastin and IFN-alpha are approximately 25 % higher than those with interferon alone. Response rates have been reported to be improved by combining IFN-alpha with antineoplastic agents or other cytokines. Combination therapy with systemically administered IL2 and IFN-alpha has resulted in long-term remissions in 30 % of patients with metastatic renal cell carcinoma.

Treatment of CML with IFN-alpha causes hematological remissions in most patients and has been shown to cause a complete elimination of the PH1-(Philadelphia chromosome)-positive cells in the bone marrow of some patients.

Prospective studies are now under way to evaluate the effectiveness of IFN-alpha in the treatment of non-Hodgkin lymphomas, cutaneous T-cell lymphomas (Mycosis fungoides, Sézary syndrome), multiple myelomas, condylomata acuminata and chronic active hepatitis B.

Some patients treated with genetically engineered recombinant IFN-alpha-2 (see also: Recombinant cytokines) have been shown to develop neutralizing antibodies against interferon. Increasing levels of antibodies correlate with increasing reoccurrence of the disease. Therefore, patients should be monitored for the presence and clinical relevance of IFN-alpha antibodies to determine those who could respond to alternative treatment. It has been assumed that the recombinant protein (see also: Recombinant cytokines) may possess an altered tertiary structure leading to the exposure of a novel immunoreactive epitope not normally recognized in natural IFN-alpha. Continuation of the treatment with natural purified IFN-alpha leads to the disappearance of antibodies and also causes remissions.

In many instances a combination of the various interferons (see: IFN) has been found to cause synergistic effects. The antiviral/antiproliferative/antitumor properties of IFN-alpha is potentiated by febrile temperatures.



 

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