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Interferon Alpha
Interferon Alpha
Introduction
I chose this set of molecules because I knew about the drug Interferonalpha-2a and its immunomodulatory properties. This drug is popular in
time of season flu to prevent the disease. I was interested in the action
mechanism of this molecule and its the drawbacks. But it appeared that
there is a family of interferon-alpha, and there are plenty of drugs, that are
proteins of this family or their combinations. This topic appeared to be so
complex, that I I put the main focus on the differences between proteins
and their subgroups inside interferon-alpha group [Hilkens 2003, Molla
2011]. The section Differences in IFN-alpha subtypes is devoted to the
analysis of these studies.
Interferons family
IFNs belong to the large class of glycoproteins known as cytokines.
Interferons are ubiquitous cytokines. They are produced by all
mononuclear cell types in response to infection by a DNA or RNA virus.
Interferons are named after their ability to "interfere" with viral replication
within host cells. IFNs have other functions: they activate immune cells,
such as natural killer cells and macrophages; they increase recognition of
infection or tumor cells by up-regulating antigen presentation to T
lymphocytes; and they increase the ability of uninfected host cells to resist
new infection by virus. Certain host symptoms, such as aching muscles
and fever, are related to the production of IFNs during infection [Meyer
2009, Borden 2007], [19].
IFN milik kelas besar glikoprotein yang dikenal sebagai sitokin. Interferon
adalah sitokin mana-mana. Mereka diproduksi oleh semua jenis sel
mononuklear dalam menanggapi infeksi oleh virus DNA atau RNA.
Interferon yang dinamai kemampuan mereka untuk "mengganggu"
dengan replikasi virus dalam sel inang. IFN memiliki fungsi lain: mereka
mengaktifkan sel-sel kekebalan tubuh, seperti sel-sel pembunuh alami dan
makrofag; mereka meningkatkan pengakuan infeksi atau tumor sel
dengan up-mengatur presentasi antigen ke limfosit T; dan mereka
meningkatkan kemampuan sel inang terinfeksi untuk melawan infeksi
baru oleh virus. Gejala tuan rumah tertentu, seperti sakit otot dan demam,
terkait dengan produksi IFN selama infeksi [Meyer 2009, Borden 2007],
[19].
About ten distinct IFNs have been identified in mammals; seven of these
have been described for humans. Based on the type of receptor through
which they signal, human interferons have been classified into three major
types: Type I IFN, Type II IFN, and Type III IFN. Type I or nonimmune
Interferon-alpha group
The main type I interferons present in humans are IFN- and IFN- (others
are IFN-, IFN-, IFN-) [Pestka, 2004]. In humans there are multiple IFN-
genes and a single gene of each of IFN-, IFN-, IFN-, IFN-. A total of 14
human non-allelic IFN- genes are located on the short arm of
chromosome 9, given rise to 12 distinct proteins (IFN-1, IFN-2a, IFN2b,IFN-4a, IFN-4b, IFN-5, IFN-6, IFN-7, IFN-8, IFN-10, IFN-14,
IFN-16, IFN-21) [REF]. At least 13 IFN- genes are transcribed. The
coding sequences of those genes diverge up to 8% giving rise to 12
different functional subtype proteins (proteins IFN-1 and IFN-13 are
identical) [Pestka 2004, Hilkens 2003].
Jenis utama saya Interferon hadir pada manusia adalah IFN- dan IFN-
(orang lain IFN-, IFN-, IFN-) [Pestka, 2004]. Pada manusia ada
beberapa gen IFN- dan sebuah gen tunggal dari masing-masing IFN-,
IFN-, IFN-, IFN-. Sebanyak 14 non-alelik gen IFN- manusia terletak
pada lengan pendek kromosom 9, melahirkan 12 protein yang berbeda
(IFN-1, IFN-2a, IFN-2b, IFN-4a, IFN-4b, IFN -5, IFN-6, IFN-7, IFN8, IFN-10, IFN-14, IFN-16, IFN-21) [REF]. Setidaknya 13 gen IFN-
ditranskripsi. Urutan coding dari gen-gen menyimpang hingga 8%
sehingga menimbulkan 12 protein yang berbeda subtipe fungsional
(protein IFN-1 dan IFN-13 identik) [Pestka 2004, Hilkens 2003].
All type I IFNs are structurally similar and share a common receptor IFNAR,
consisting of two known subunits, IFNAR1 and IFNAR2. Binding and
activation of the receptor stimulates Janus protein kinases, which in turn
phosphorylate several proteins, including STAT1 and STAT2 and leads to
downstream signaling events. Activated ISGF3 (IFN-stimulated gene factor
3) consisting of STAT1, STAT2 and the IRF-9 (IFN regulatory factor 9) binds
to IFN-stimulated response elements (ISREs). The result is transcriptional
activation of numerous IFN-stimulated genes (ISGs). The resulting proteins
mediate the biological responses generally attributed to type I IFN,
including antiviral, antiproliferative and immuneregulatory activities [REF]
[Pestka 2004, Hilkens 2003].
Semua IFN tipe I secara struktural mirip dan berbagi IFNAR reseptor
umum, yang terdiri dari dua subunit dikenal, IFNAR1 dan IFNAR2. Mengikat
dan aktivasi reseptor merangsang Janus protein kinase, yang pada
Despite the fact, that IFN- proteins share the same receptor, the specific
activity of individual IFN-alpha proteins differs. It might be due to distinct
receptor affinity and\or different interaction sites and it can lead to the
variability of signals transduced. Regarding the signaling events triggered
by IFN- subtypes there are indication for differential receptor interaction
and distinct activation of STAT molecules, which may result in divergent
ISG regulation and functional impact on the IFN- family members. With
respect to cell responses triggered by IFN- versus IFN-, a distinct
aminoacid composition conserved among IFN- subtypes seems to result
in a weaker affinity for IFNAR1 and a generally lower biological activity of
the IFN- subtypes. However, differences in gene regulation by IFN-
versus IFN- are only detectable at subsaturating concentrations,
indicating that responses comparable to IFN- may be elicited by high
levels of IFN- [Hilkens 2003, Molla 20111].
Terlepas dari kenyataan, bahwa protein IFN- berbagi reseptor yang
sama, aktivitas spesifik protein IFN-alpha individu berbeda. Ini mungkin
disebabkan karena afinitas reseptor yang berbeda dan \ atau situs
interaksi yang berbeda dan dapat menyebabkan variabilitas sinyal
tertransduksi. Mengenai peristiwa sinyal dipicu oleh subtipe IFN- ada
indikasi untuk interaksi reseptor diferensial dan aktivasi yang berbeda dari
molekul STAT, yang dapat mengakibatkan regulasi ISG berbeda dan
dampaknya fungsional pada anggota keluarga IFN-. Sehubungan dengan
respon sel dipicu oleh IFN- dibandingkan IFN-, komposisi asam amino
yang berbeda dilestarikan antara subtipe IFN- tampaknya menghasilkan
afinitas lemah untuk IFNAR1 dan aktivitas biologis umumnya lebih rendah
dari subtipe IFN-. Namun, perbedaan dalam regulasi gen oleh IFN-
dibandingkan IFN- hanya terdeteksi pada konsentrasi sub jenuh, yang
menunjukkan bahwa tanggapan sebanding dengan IFN- dapat
ditimbulkan oleh tingkat tinggi IFN- [Hilkens 2003, Molla 20111].
Producers of interferon-alpha
An important consequence of having several type I IFN might lie in the
different temporal or spatial regulation of their expression. It seems
probable that all cells produce IFNs I after viral infections. Similarly, cells
of epithelial, fibroblast or hematopoietic origin produce IFNs I in response
to bacterial infection. In general interferons alpha are produced by
Setelah infeksi virus, PDC / IPC cepat menghasilkan sejumlah besar tipe 1
IFN, yang tidak hanya memiliki efek penghambatan langsung pada
replikasi virus tetapi juga berkontribusi pada aktivasi sel NK, sel B, sel T,
dan mDCs, menyebabkan induksi dan perluasan respon imun antivirus.
Kemampuan diaktifkan PDC / IPC untuk mengaktifkan myeloid belum
menghasilkan DC melalui tipe 1 IFN tampaknya menjadi penting untuk
induksi imunitas antiviral diperantarai sel T.
After producing large amounts of type 1 IFN at a later stage of viral
infection pDC/IPCs rapidly differentiate into unique type of mature DCs
through an autocrine mechanism mediated by type 1 IFNs and TNF-. At
this stage, pDC/IPC-derived DCs may contribute to the contraction of the
effector phase of T cell responses and at the same time to the
establishment of T cell memory. These mature dendritic cells regulate the
function of T cells and thus links innate and adaptive immune responses.
IPCs are considered as the most important cell type in antiviral innate
immunity.
Setelah memproduksi sejumlah besar tipe 1 IFN pada tahap berikutnya
dari infeksi virus PDC / IPC cepat berdiferensiasi menjadi jenis yang unik
dari DC matang melalui mekanisme autokrin dimediasi oleh tipe 1 IFN dan
TNF-. Pada tahap ini, PDC / IPC yang diturunkan DC dapat berkontribusi
pada kontraksi fase efektor dari respon sel T dan pada saat yang sama
untuk pembentukan memori sel T. Sel-sel dendritik matang mengatur
fungsi sel T dan dengan demikian menghubungkan respon imun bawaan
dan adaptif. IPC dianggap sebagai jenis sel yang paling penting dalam
imunitas bawaan antivirus.
(e.g. antiviral effects) as they act through the common receptor. However,
there is substantial biochemical evidence that individual IFN- subtypes
bind to different sites of IFN-R (IFN- receptor) and have different
binding affinities. This leads to the formation of distinct signaling
complexes, which might be expected to differentially recruit downstream
signaling pathways [Hilkens 2003, Molla 2011].
Keberadaan begitu banyak subtipe IFN- yang berbeda menimbulkan
pertanyaan relevansi biologis mereka. Hal ini diketahui bahwa virus yang
berbeda menyebabkan pola yang berbeda dari IFN- ekspresi subtipe dan
bahwa produksi subtipe individu diatur oleh IRF berbeda (interferonmengatur gen). Potensi relatif berbeda telah ditunjukkan, namun, semua
subtipe IFN- mungkin memiliki kemampuan untuk mengerahkan kegiatan
IFN- klasik (misalnya efek antivirus) karena mereka bertindak melalui
reseptor umum. Namun, ada bukti biokimia substansial bahwa individu
subtipe IFN- mengikat ke situs yang berbeda dari IFN-R (reseptor IFN) dan memiliki afinitas mengikat yang berbeda. Hal ini menyebabkan
pembentukan kompleks sinyal yang berbeda, yang mungkin diharapkan
untuk secara berbeda merekrut jalur sinyal hilir [Hilkens 2003, Molla
2011].
In the study [Hilkens, 2003] for the first time was investigated the
specificity of IFN-alpha responses in immune cells (T cells and Dendritic
cells in particular. Signaling through the Jak/STAT pathways and gene
expression profiles were examined for human T cells and DC treated with
different IFN- subtypes. The authors supposed that super-imposed upon
widely overlapping classical functions such subtype specific signaling
complexes may be capable of differentially activating ancillary responses
peculiar to that subtype. It was assumed that the differences between
IFN- subtype signaling vary with cellular background and will be
manifested by differentials in gene expression profiles. These cells were
chosen because it seems most obvious to analyze IFN- subtype
properties in primary cells of the immune system. The following subtypes
of IFN- were chosen for the analysis: IFN-1, IFN-2 and IFN-2 because
IFN-1 and IFN-2 are generally the major IFN-species produced in
response to many viruses and are widely used therapeutically. Also IFN21 exhibits enhanced growth inhibitory activity compare with IFN-2. In
addition both recombinant and natural IFN-1 have a ~10 fold lower
specific antiviral activity that the majority of subtypes, including IFN-21
and IFN-2.
Dalam studi [Hilkens 2003] untuk pertama kalinya diselidiki kekhususan
tanggapan IFN-alpha di sel kekebalan (sel T dan sel dendritik pada
khususnya. Signaling melalui jalur Jak / STAT dan profil ekspresi gen
diperiksa untuk sel T manusia dan DC diperlakukan dengan berbeda
subtipe IFN-. Para penulis seharusnya yang super-dibebankan pada
fungsi klasik banyak tumpang tindih subtipe seperti kompleks sinyal
tertentu mungkin mampu secara berbeda mengaktifkan respon tambahan
semua ini IFN- dalam sel T. Selain peran protektif untuk IP-10 pada
infeksi yang memerlukan respon imun yang kuat diperantarai sel, juga
dapat berkontribusi untuk perkembangan beberapa penyakit. Ekspresi IP10 telah diamati di banyak Th1-jenis penyakit autoimun / inflamasi
termasuk psoriases, multiple sclerosis, rheumatoid arthritis dan diabetes
type1 [Meyer 2009 ], di mana perekrutan berikutnya sel Th1 ke situs
inflamasi yang tidak diinginkan. Hal ini menarik untuk dicatat bahwa
aplikasi terapi IFN- yang contraidicated pada pasien dengan riwayat
gangguan Th1 terkait. Ada contoh klinis di mana administrasi IFN- telah
menyebabkan induksi penyakit auto-imun dan telah menyebabkan
eksaserbasi lesi psoriatik [Meyer 2009]. Menerima peran penting dari IP-10
di Th1 tipe penyakit radang pengamatan regulasi diferensial sebesar
subtipe IFN- mungkin relevan secara klinis. The IFN-1 subtipe mungkin
calon lebih cocok untuk aplikasi terapeutik dalam kasus di mana respon
inflamasi Th1 yang tidak diinginkan sebagai induksi IP-10 jauh lebih sedikit
dalam menanggapi IFN-1. Juga itu menggoda bahwa IFN-1
menyebabkan efek samping yang kurang pada pasien dengan penyakit
ganas.
The study [Moll, 2011] addressed to the diversity of IFN- subtypes in the
context of cell-type specific responses in a comprehensive manner. It was
shown that differential activity of interferon-alpha subtypes is consistent
among distinct target genes and cell types. ISG regulation at the mRNA
and protein level as well as anti-viral activity were investigated in
lymphatic endothelial cells (LECs), in blood vessel endothelial cells (BECs)
and in primary fibroblasts isolated from the same donor to minimize the
role of biological variation.
Studi [Moll, 2011] yang ditujukan kepada keragaman subtipe IFN- dalam
konteks sel-jenis tanggapan khusus secara komprehensif. Hal ini
menunjukkan bahwa aktivitas diferensial dari subtipe interferon-alpha
konsisten antara gen target yang berbeda dan jenis sel. Peraturan ISG di
mRNA dan tingkat protein serta aktivitas anti-viral diselidiki dalam sel
endotel limfatik (LEC), di sel endotel pembuluh darah (KBG) dan di
Enzyme oligoadenylate synthetase, which polymerazes ATP into 2'5'-linked oligomers. These activate an endoribonuclease that then
degrades viral RNA.
Future
In recent decades the structure and the function of interferons (IFNs) have
been elucidated and it is now clear that IFN is not only a protein but a
group of proteins with parallel, but not analogous or identical, biochemical
and biological properties. Among them there are at least 12 subtypes of
IFN-alpha which are all involved in the control of several cellular functions
and are all actively engaged in host defense mechanisms against
infections. These acquisitions led to the clinical use of different types of
IFN-alpha with appreciable success in several diseases. There are however
several possibilities to optimize IFN-alpha treatment which can and must
be addressed. For instance, as regards IFN-alpha biology and therapy
issues, we need to understand more how the different subtypes can
generate similar signaling outputs but also govern specific cellular
responses and more in general why the body produces so many of these
IFN-alphas.
Dalam beberapa dekade terakhir struktur dan fungsi interferon (IFN) telah
dijelaskan dan sekarang jelas bahwa IFN tidak hanya protein tetapi
References
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Differential responses to IFN-alpha subtypes in human T cells and dendritic
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Hilkens CM, Schlaak JF, Kerr IM.
2. Cytokine. 2011 January ; 53(1): 5259.
The differential activity of interferon- subtypes is consistent
among distinct target genes and cell types
Herwig P. Molla, Thomas Maiera, Anna Zommera, Thomas Lavoieb, and
Christine
Brostjana
3. Nature Reviews Immunology 8, 559-568 (July 2008) |
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