RESEPTOR SITOKIN

DEWI GULYLA HARI

132 101 2002

Apa Itu Reseptor

Sitokin?

Cytokines: main
functions

Hematopoiesis (ex. CSFs, colony stimulating

factors).

Inflammatory reaction (ex. IL1, TNF).

Chemotaxis (ex. IL8, MIP1- macrophage inflammatory

protein 1, BLC B-lymphocyte chemoatractant).

Immunostimulation (ex. IL12, IFN).

Suppression (ex. IL10).

Angiogenesis (ex. VEGFs - vacsular endothelial growth

factor).

Embryogenesis (ex. TGF-, LT - lymphotoxin).

Cytokine
nomenclature
Lymfokines - produced by activated T
lymphocytes direct the immune system
response by signaling between its cells

Interleukins - presumed targets are

principally leukocytes.

Chemokines - specific class of cytokines.

Mediates chemoattraction (chemotaxis)

between cells, stimulate leukocyte movement
and regulate the migration of leukocytes from
the blood to tissues.

Monokines - derived primarily from

Type I cytokine receptor

Transmembrane
receptors expressed
on the surface of
cells.
These receptors are
also known under
the name
hematopoetin
receptors, and
share a Trp-Ser-XSer-Trp motif
(WSXWS) in the
extracellular portion

Common chain

The chain (green), common to all,

mediates intracellular signaling.

Signaling through cytokine receptor

Phosphorylation through kinases:

The

addition of a phosphate molecule to a polar

R- group of Tyr can turn a hydrophobic portion of
protein into a polar and extreme hydrophilic
portion of molecule.
Kinase is a type of enzyme that transfers phosphate
group (PO4) from high-energy donor molecules, such as
ATP to specific target molecules (substrates).
The opposite, an enzyme that removes phosphate
groups from targets, is known as a phosphatase.
Kinase enzymes that specifically phosphorylate tyrosine
amino acids are termed tyrosine kinases.

Signaling through cytokine

receptor

The ligand-activated receptor (R) attracts a Janus (JAK) kinase (K). K

phosphorylates both itself and the receptor. A Signal Transducer and
Activator of Transkription (STAT) protein (S) binds to tyrosinephosphorylated receptor-kinase complex. After being phosphorylated by
JAK, the STATs form active dimers that translocate into the nucleus to

Type II cytokine receptors

Interferons (IFN)

Protein hormones with antiviral activity.

Secrete by cells in a response to variety of

stimuli.

Type I and type II IFN and IFN-like cytokines.

Effects are mediated through cell receptors.

IFN activate cellular signalling pathway (gene

induction or repression).

Type I IFNs consist of seven classes:

IFN-, IFN-, IFN-, IFN-, IFN-
IFN-and IFN-
Type I IFNs are major components of the
innate immune system.
Protect against viral infection.
The expression of type I IFNs is induced by
viral challenge.

Type II IFN consist of IFN- only.

IFN- (immune interferon) is produced by
certain activated T-cells and NK cells.
IFN- is made in response to antigen
(including viral
antigens) or mitogen
stimulation of lymphocytes.

Type I IFNs
Produced by macrophages, neutrophils and
other somatic cells in response to infection by
viruses or bacteria.
Inducer is double strand RNA provided by
viral genom itself.
Receptors are expressed on most cell types.

IFN-
IFN- is produced in activated TH1 and NK
cells, particularly in response to IL-2 and IL-12.
Binding of IFN- to its receptor increases the
expression of class I MHC on all somatic cells.
IFN- may also activate macrophages,
neutrophils and NK cells.

Function of IFNs:
Initiation and
regulation of
variety responses

antiviral

antiproliferative
activity (ability to
arrest cell growth)
treatment for cancer

control of
apoptosis

immunomodulatory
(INF- predominantly
modulates immune

http://www.virtualsciencefair.org/2007/sank7b2/fig1b.jpg

IFN- receptor
Expression of on the surface almost of
all cell types.

High affinity receptors are located in the

T- and
B-lymphocytes, NKcells, monocytes, macrophages,
neutrophiles, fibroblasts, endotelial cells
and smooth muscle cells.

Receptor is expressed only in response

to stimulus by antigen, only in cells of
lymphoid origin (NK cells, macrophages,
and some T cells).

IFNreceptor has two

components:
R1 and R2
IFN- R1 - 90 kDa glycoprotein (472 amino
acid residues)
Extracellular domain 228 amino acid
residues
Transmembrane domain 24 amino acid
residues
Intracellular domain 220 amino acid
residues
IFN- R2 - 62 kDa glycoprotein (315
amino acid residues)
Extracellular domain 226 amino acid
residues
Transmembrane domain 23 amino acid
residues
Intracellular domain 65 amino acid
residues.

Ligand binds to extracellular domain of

IFN-R1 only (in absence of IFN-R1,
IFN-R2 cannot bind IFN

Signal transduction is carried out through a

series of tyrosine phosphorylation events and
culminates with the activation and nuclear
translocation of STAT protein and new mRNA
is induced.
Jak proteins are brought
into close
synthesis
after ligand-receptor complex
formation.
Transphosphorylation between Jak1
and Jak2 proteins (Jak2 phosphorylates
Jak1, Jak1 transphosphorylates Jak2).
phosphorylation of IFN-R1 (Tyr
440).
Binding of STAT1 protein to each
IFN-R1.
Bound Sis phosphorylated by
Jak.
Dissociation of dimer from the
receptor and formed dimer translocates
to the nucleus.
Induction of transcription of many
genes.

IFN receptor
IFN- R1 - 530 amino acid
residues (409 residues of protein are
extracellular, 100 residues are
intracellular.

IFN- R2 - 217 AA residues in

extracellular space, 251 AA residues
in intracellular space.

Both components bind type-IFNs

cooperatively.
Receptor has ability to bind
multiple ligands (all subspecies of
IFN- and IFN- and other types of
IFN-type I).
Interferon ligand is boud to IFNR1 and than to IFN-R2 which
stabilizes the complex.

Signal transduction goes through Jak/STAT

pathway.
Involves two different ligand binding proteins
Tyk2 associates with IFN-R1(kinases)
Jak1, STAT1 and STAT2 associate
Tyk2 and Jak1.
with IFN-R2.

Jak1 transphosphorylates Tyk2 (1).

Tyk2 in turn phosphorylates Jak1 and
IFN-R1 (2).

Phosphorylation of IFN-R1 allows

STAT2 to bind to IFN-R2.

STAT2 phoshorylates STAT1.

STAT1-STAT2 complex dissociates
from receptor.

Dimer STAT1-STAT2 associates with

interferon regulatory factor to form
the transcription complex.

Effect of signalling through IFN- receptor

Induces inflammatory reaction.

Induces antibacterial effect (activation of

neutrophils, NK cells and macrophages,
increased their ability to recognize, kill, and
digest foreign materials or microbes).

Normal expression of is important in

preventing the development of cancer.

Effect of signalling through IFN-/ receptor

Antiviral defence (protects the cell from viral
replication).

Immunoglobulin superfamily (IgSF)

The immunoglobulin
superfamily (IgSF) - a large
group of cell surface and
soluble proteins that are
involved in the recognition,
binding, or adhesion
processes of cells.

Molecules are categorized

as members of this
superfamily based on shared
structural features with
immunoglobulins (antibodies);
they all possess a domain
known as an immunoglobulin
domain or fold.

Associated with roles in the

Tumor Necrosis Factor receptor

Cysteine-rich common
extracellular binding domain

Chemokine receptor
Typical structure of a
chemokine receptor, with
seven transmembrane
domains. Chemokine receptors
are usually linked to a G-protein
through which they signal.
Interaction with their specific
chemokine ligand, chemokine
receptors
trigger a flux in
http://en.wikipedia.org/wiki/Chemokine_receptor
intracellular calcium (Ca2+)

Transforming Growth Factor Receptor

After ligand binding, (PDGFR or
EGFR receptor tyrosine kinases (RTKs)
dimerize, undergo
autophosphorylation (P) and recruit
adaptor proteins (such as GRB2 and
SHC) that activate various
downstream effectors.

RAS is an important downstream

effector and functions as a molecular
switch by cycling between the active
GTP-bound form and the inactive
GDP-bound form. RAS activity is
regulated positively by guanosine
exchange factors (GEFs), such as
SOS, and negatively by GTPaseactivating proteins (GAPs).

www.nature.com/.../v2/n8/fig_tab/nrc866_F3.html

OMALIZUMAB,
AN OVER VIEW STUDY

PENDAHULUAN
Omalizumab

adalah
rekombinan
monoklonal
antibodi
yang
terkait
langsung melawan IgE , dalam implikasi
alergi asma
Melalui pembentukan kompleks dengan
IgE, omalizumab dapat mengurangi
ekserbasi akibat asma sehingga sangat
bermanfaat dalam mengobati asma
ringan sampai sedang
Salah satu bentuk komersial produk ini
adalah XOLAIR

INDIKASI

Omalizumab (XOLAIR) diizinkan oleh

FDA tahun 2003 untuk mengobati asma
ringan sampai sedang untuk pasien 12
th ke atas.

Bukti-bukti
menunjukkan
bahwa
omalizumab
dapat
mengurangi
eksaserbasi
asma
atau
kejadian
konstriksi
jalan
nafas
yang
menyebabkan batuk, susah bernafas
dan wheezing.

MEKANISME KERJA
Omalizumab
terikat
secara
selektif dengan IgE sehingga
dapat menghambat ikatan IgE
dengan FCERI pada permukaan sel
mast dan basofil, yang pada
akhirnya
dapat
mengurangi
pelepasan mediator inflamasi

Absorpsi
Omalizumab

memiliki
bioavalaibilitas rata-rata 62%

Konsentrasi

serum puncak masih

dapat diamati 7-8 hari setelah
pemberian secara sub cutan

Distribusi
Volume

distribusi omalizumab
adalah 78 + 32 mL/kg

Kebanyakan

senyawa obat akan

berada
dalam
kompartemen
sentral intramuscular, tanpa ada
bukti
bahwa
mereka
juga
terdistribusi dalam organ atau
jaringan lainnya

Metabolisme & Eliminasi

Waktu

paruh omalizumab adalah 26 hari

dengan laju clearence 2,4 + 1,1
mL/kg/hari pada pasien asma

Omalizumab

dieliminasi
melalui
degradasi pada sistem retikuloendotelial
hati dan endotelial sel

Eksresi

empedu

senyawa

ini

dilakukan

oleh

DOSIS

DOSIS (lanjutan)

PERINGATAN & PERHATIAN

Thank You