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Pathway Description
Interferon beta-1a Action Pathway
Homo sapiens
Drug Action Pathway
Interferon beta-1a is a recombinant form of the human interferon. It is used to slow disease progression and reduce the clinical symptoms of patients with relapsing multiple sclerosis (RMS). It can also be used for condyloma acuminatum. Interferon beta-1a binds to type 1 interferon receptors (IFNAR and IFNAR2c). This drug activates the dimerization of these receptors. This action activates the Jak tyrosine kinases (Jak1 and Tyk2). These transphosphorylate themselves and phosphorylate the IFNAR and IFNAR2c. This receptor complex also phosphorylates STAT3 homodimers. The IFNAR complex phosphorylates STAT5 which binds with Crk-like protein (CRKL). This activates the transcription of gamma-activated sequence (GAS) elements, which activates an inflammatory response and immunoregulation. When phosphorylated, the receptors bind to Stat1 and Stat2, and together with the interferon regulatory factor (IRF9) they form the interferon-stimulated gene factor 3 (ISGF3). The ISGF3 translocates to the nucleus to initiate the transcription of the Interferon-sensitive response element (ISRE). This leads to an antiviral response, immunoregulation, antigen presentation, and checkpoint proteins. The ISRE genes also activate IFN-regulated genes. These along with lipopolysaccharides or foreign pathogens activates interferon Regulatory Factor 7 (IRF7). IRF7 is phosphorylated and bound with nuclear factor kappa B (NFKB). This causes the induction of type 1 INFs, which further activates the JAK/STAT pathway. IFNAR1 and IFNAR2 signal through TYK2 and JAK1 also trigger the activation of the NFKB pathway through phosphorylated STAT3, phosphoinositide 3-kinase (PI3K), protein kinase B (AKT), and TNF receptor-associated factors (TRAFs). They act through IKKa and IKKb to drive NFKB induction of genes associated with survival signals, antigen processing and presentation, and proliferation.
References
Interferon beta-1a Pathway References
Wishart DS, Feunang YD, Guo AC, Lo EJ, Marcu A, Grant JR, Sajed T, Johnson D, Li C, Sayeeda Z, Assempour N, Iynkkaran I, Liu Y, Maciejewski A, Gale N, Wilson A, Chin L, Cummings R, Le D, Pon A, Knox C, Wilson M: DrugBank 5.0: a major update to the DrugBank database for 2018. Nucleic Acids Res. 2018 Jan 4;46(D1):D1074-D1082. doi: 10.1093/nar/gkx1037.
Pubmed: 29126136
Russell-Harde D, Wagner TC, Perez HD, Croze E: Formation of a uniquely stable type I interferon receptor complex by interferon beta is dependent upon particular interactions between interferon beta and its receptor and independent of tyrosine phosphorylation. Biochem Biophys Res Commun. 1999 Feb 16;255(2):539-44. doi: 10.1006/bbrc.1998.0105.
Pubmed: 10049744
van Koetsveld PM, Vitale G, de Herder WW, Feelders RA, van der Wansem K, Waaijers M, van Eijck CH, Speel EJ, Croze E, van der Lely AJ, Lamberts SW, Hofland LJ: Potent inhibitory effects of type I interferons on human adrenocortical carcinoma cell growth. J Clin Endocrinol Metab. 2006 Nov;91(11):4537-43. doi: 10.1210/jc.2006-0620. Epub 2006 Aug 15.
Pubmed: 16912135
Dupont SA, Goelz S, Goyal J, Green M: Mechanisms for regulation of cellular responsiveness to human IFN-beta1a. J Interferon Cytokine Res. 2002 Apr;22(4):491-501. doi: 10.1089/10799900252952280.
Pubmed: 12034032
Runkel L, De Dios C, Karpusas M, Baker D, Li Z, Zafari M, Betzenhauser M, Muldowney C, Miller S, Redlich PN, Grossberg SE, Whitty A, Hochman PS: Mapping of IFN-beta epitopes important for receptor binding and biologic activation: comparison of results achieved using antibody-based methods and alanine substitution mutagenesis. J Interferon Cytokine Res. 2001 Nov;21(11):931-41. doi: 10.1089/107999001753289541.
Pubmed: 11747625
Owen KL, Brockwell NK, Parker BS: JAK-STAT Signaling: A Double-Edged Sword of Immune Regulation and Cancer Progression. Cancers (Basel). 2019 Dec 12;11(12):2002. doi: 10.3390/cancers11122002.
Pubmed: 31842362
Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. doi: 10.1093/nar/30.1.412.
Pubmed: 11752352
Markowitz CE: Interferon-beta: mechanism of action and dosing issues. Neurology. 2007 Jun 12;68(24 Suppl 4):S8-11. doi: 10.1212/01.wnl.0000277703.74115.d2.
Pubmed: 17562848
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