otras citoquinas

Las Citocinas (III)
Dr. Juan Rodríguez-Tafur D.
Profesor Asociado de Farmacología e Inmunología
Laboratorio de Farmacología de la Respuesta Inmune
Coordinador del Comité de Residentado Médico de
Inmunología Clinica y Alergología
Facultad de Medicina – UNMSM
Lima (Perú)
Agosto 2005
OTRAS CITOQUINAS
1
INTERLEUQUINA-7 (IL-7)
INTERLEUQUINA-7 (IL-7)
GLICOPROTEINA DE 25 KD
GLICOPROTEINA DE 25 KD
ES PRODUCIDA EN EL TIMO, EL BAZO Y CELULAS ESTROMAL DE LA M.O.
ES PRODUCIDA EN EL TIMO, EL BAZO Y CELULAS ESTROMAL DE LA M.O.
MEJORA LA ADHESION DE β INTEGRINAS DEL TIMOCITO A LA MATRIX PROTEICA
MEJORA LA ADHESION DE β INTEGRINAS DEL TIMOCITO A LA MATRIX PROTEICA
MITOGENO (CON SCF) DE TIMOCITOS Y CEL PRE-B
MITOGENO (CON SCF) DE TIMOCITOS Y CEL PRE-B
MEJORA LA FUNCION DE CEL. CITOTOXICAS
MEJORA LA FUNCION DE CEL. CITOTOXICAS
DEFICIT EN ANIMALES PRODUCE HIPOPLASIA LINFOIDE DE CELULAS T Y B.
DEFICIT EN ANIMALES PRODUCE HIPOPLASIA LINFOIDE DE CELULAS T Y B.
2
PROTEINA
PROTEINA DE
DE 19
19 KD
KD
ACTUA
ACTUA COMO
COMO FACTOR
FACTOR DE
DE CRECIMIENTO
CRECIMIENTO DE
DE CELULAS
CELULAS
BLASTICAS
BLASTICAS
SINERGISMO
SINERGISMO CON
CON IL-3,
IL-3, IL-4,
IL-4, CSF-GM
CSF-GM
ROL
ROL IMPORTANTE
IMPORTANTE EL
EL HEMATOPOIESIS,
HEMATOPOIESIS, LINFOPOIESIS,
LINFOPOIESIS,
DESARROLLO
DESARROLLO DE
DE ADIPOCITOS,
ADIPOCITOS,
NEURONAS
NEURONAS Y
Y OSTEOCLASTOS
OSTEOCLASTOS
CON
CON IL-3
IL-3 INCREMENTAN
INCREMENTAN EL
EL NUMERO
NUMERO Y
Y TAMAÑO
TAMAÑO DE
DE LAS
LAS
COLONIAS
COLONIAS DE
DE MEGACARIOCITOS
MEGACARIOCITOS
Nordan
Nordan RP,
RP, Potter
Potter M
M Science
Science 233(4763):566-9
233(4763):566-9 (1986)
(1986)
Paul
Paul SR
SR yy col.
col. Proc.
Proc. Natl.
Natl. Acad.
Acad. Sci.
Sci. USA
USA 87:7512
87:7512 (1990)
(1990)
HETERODIMERO
HETERODIMERO DE
DE 22 SUBUNIDADES
SUBUNIDADES DE
DE 35
35 Y
Y 40
40 KD
KD
LA
LA PRODUCC.
PRODUCC. DE
DE IL-12
IL-12 ES
ES ACTV.
ACTV. POR
POR MACROFAGOS
MACROFAGOS
Y
Y ES
ES INHIBIDO
INHIBIDO POR
POR IL-4
IL-4 Y
Y POR
POR IL-10
IL-10
INDUCE
INDUCE PRODUCCION
PRODUCCION DE
DE IFN-γ,
IFN-γ, PROMUEVE
PROMUEVE LA
LA PROLIF.
PROLIF. DE
DE CEL
CEL TT ACTV.
ACTV.
Y
NK
Y CEL.
CEL. NK
INDUCE
INDUCE TH-O
TH-O A
A TH-1
TH-1 SUPRIME
SUPRIME TH-2
TH-2 INDUCE
INDUCE PRODUCION
PRODUCION DE
DE CSF-GM,
CSF-GM,
TNF,
TNF, IL-6
IL-6 ,, EN
EN MENOR
MENOR PROPORCION
PROPORCION IL-2
IL-2 (ACCION
(ACCION SINERGICA
SINERGICA CON
CON IL-2)
IL-2)
Gately
Gatelyyycol.
col. J.J.Immunol.
Immunol.136,1274-1281
136,1274-1281(1986)
(1986)
Wong
y
col.
Cell
Immunol.
Wong y col. Cell Immunol.111,39-54
111,39-54(1987)
(1987)
3
GLICOPROTEINA
GLICOPROTEINA DE
DE 50-60
50-60 KD
KD ANTES
ANTES CONOCIDO
CONOCIDO
COMO
COMO FACT.
FACT. DE
DE CRECIMIENTO
CRECIMIENTO DE
DE CELULAS
CELULAS B
B DE
DE
ALTO
PRODUCIDA
ALTO PESO
PESO MOLECULAR
MOLECULAR ES
ES
PRODUCIDA POR
POR
CEL.
CEL. DENDRITICAS
DENDRITICAS FOLICULARES
FOLICULARES Y
Y CELULAS
CELULAS T
T
ES
ES MITOGENO
MITOGENO DE
DE CELULAS
CELULAS B
B ACTIVADAS
ACTIVADAS
Pre
Pre -- B
B
IL-14
IL-14
TT
Céls dendríticas
foliculares
B
B
memoria
memoria
Ambrus,J.L.
Ambrus,J.L.and
andFauci,A.S.
Fauci,A.S. J.J.Clin.
Clin.Invest.
Invest. 75,732-739
75,732-739(1985)
(1985)
INTERLEUQUINA-15
INTERLEUQUINA-15 (IL-15)
(IL-15)
PRODUCIDO
PRODUCIDOPOR
PORCEL.
CEL.EPITELIALES
EPITELIALESYYMONOCITOS
MONOCITOS
PERO
NO
POR
LINFOCITOS
PERO NO POR LINFOCITOSTT
INDUCE
INDUCEPROLIF
PROLIFDE
DECEL
CELTTACTIVAS
ACTIVAS
GENERA
GENERACEL
CELTTCITOTOXICAS
CITOTOXICASESPECIFICAS
ESPECIFICAS
SE
SEEXPRESA
EXPRESAEN
ENPLACENTA,
PLACENTA,MUSC.
MUSC.ESQUEL,
ESQUEL,RINON,
RINON,
PULMON,
HIGADO,
CORAZON
Y
ESTROMA
PULMON, HIGADO, CORAZON Y ESTROMADE
DEM.O.
M.O.
IL-2,
IL-2,IL-4,
IL-4,IL-7,
IL-7,IL-9,
IL-9,IL-15
IL-15COMPATEN
COMPATENEL
ELRECEPTOR
RECEPTOR
(IL-2Rγ,
SU
DEFICIENCIA
PRODUCE
X-SCID)
(IL-2Rγ, SU DEFICIENCIA PRODUCE X-SCID)
4
CONOCIDO
CONOCIDO ANTES
ANTES COMO
COMO LCF
LCF (FACTOR
(FACTOR
QUIMIOQUIMIOATRAYENTE
ATRAYENTE DE
DE LINFOCITOS)
LINFOCITOS)
INDUCE
INDUCE LA
LA MIGRACION
MIGRACION DIRECCIONAL
DIRECCIONAL DE
DE
CD4+,
CD4+,
EOSINOFILOS
EOSINOFILOS Y
Y MONOCITOS
MONOCITOS
↑↑ IL-2Rα
IL-2Rα
↑↑ CMH-II
CMH-II EN
EN CELULAS
CELULAS T
T
SUPRIME
INFECCION
CD8+
CD8+
HIV
IL-16
IL-16
CD4+
Kurth,
Kurth
Kurth,, R.
R. Nature
Nature Dec
Dec 1995.
1995.
PRODUCIDA
PRODUCIDA POR
POR CELULAS
CELULAS TT
ACTIVA
ACTIVA AL
AL FACTOR
FACTOR DE
DE TRANSDUCCION
TRANSDUCCION NF-κB
NF-κB
INDUCE
INDUCE LA
LA EXPRESION
EXPRESION DE
DE VARIAS
VARIAS CITOQUINAS
CITOQUINAS
PROINFLAMATORIAS
PROINFLAMATORIAS Y
Y DE
DE ICAM-1
ICAM-1
ACTUA
ACTUA SOBRE
SOBRE RECEPTORES
RECEPTORES DE
DE UNA
UNA GRAN
GRAN
VARIEDAD
VARIEDAD DE
DE CELULAS
CELULAS
Célula T
Fibroblasto
Estímulo
IL-17 (cytotoxic T-lymphocyte-associated antigen-8 CTLA-8)
5
Antígeno
INTERLEUQUINA-18
INTERLEUQUINA-18 (IL-18)
(IL-18)
PROTEINA
PROTEINADE
DE17
17KD
KD
Activación de
Macrófagos
Antígeno
PRODUCIDA
PRODUCIDAPOR
PORCEL
CELTTACTIVAS,
ACTIVAS,
ACTIVA
ACTIVACEL
CELTTYYACTUA
ACTUASOBRE
SOBRE
MUCHAS
MUCHASOTRAS
OTRASCEL
CELCOMO
COMOPROPROINFLAMATORIA
INFLAMATORIA
TAMBIEN
TAMBIENDENOMINADA
DENOMINADAFACTOR
FACTOR
INDUCTOR
INDUCTORDE
DEIFN-γ.
IFN-γ.
ESTRUCTURA
ESTRUCTURASIMILAR
SIMILARAAIL-1α,
IL-1α,
IL-1β
IL-1βEE IL-1RA
IL-1RA SE
SE PROPOSO
PROPOSO
DENOMINARLA
DENOMINARLAIL-1γ
IL-1γ
INDUCE
INDUCEIFNIFN-γγ EE INHIBE
INHIBEIL-10.
IL-10.
FUNCION
FUNCIONSIMILAR
SIMILARYYSINERGICA
SINERGICA
CON
CONIL-12
IL-12
Apoptosis de Células
que expresan FAS
6
Cell
Cell 2001
2001 Jan
Jan 12;104(1):9-19
12;104(1):9-19
Interleukin
Interleukin 20:
20: discovery,
discovery, receptor
receptor identification,
identification, and
and role
role in
in epidermal
epidermal function.
function.
Blumberg
Blumberg H,
H, Conklin
Conklin D,
D, Xu
Xu WF,
WF, Grossmann
Grossmann A,
A, Brender
Brender T,
T, Carollo
Carollo S,
S, Eagan
Eagan M,
M, Foster
Foster D,
D,
Haldeman
Haldeman BA,
BA, Hammond
Hammond A,
A, Haugen
Haugen H,
H, Jelinek
Jelinek L,
L, Kelly
Kelly JD,
JD, Madden
Madden K,
K, Maurer
Maurer MF,
MF,
Parrish-Novak
Parrish-Novak J,
J, Prunkard
Prunkard D,
D, Sexson
Sexson S,
S, Sprecher
Sprecher C,
C, Waggie
Waggie K,
K, West
West J,
J, Whitmore
Whitmore TE,
TE,
Yao
Yao L,
L, Kuechle
Kuechle MK,
MK, Dale
Dale BA,
BA, Chandrasekher
Chandrasekher YA
YA
Department
Department of
of Genetics,
Genetics, ZymoGenetics,
ZymoGenetics, Inc.,
Inc., 1201
1201 Eastlake
Eastlake Avenue
Avenue E,
E, Seattle,
Seattle, WA
WA 98102,
98102,
USA.
USA.
A
A structural,
structural, profile-based
profile-based algorithm
algorithm was
was used
used to
to identify
identify interleukin
interleukin 20
20 (IL-20),
(IL-20), aa novel
novel
IL-10
IL-10 homolog.
homolog. Chromosomal
Chromosomal localization
localization of
of IL-20
IL-20 led
led to
to the
the discovery
discovery of
of an
an IL-10
IL-10 family
family
cytokine
cytokine cluster.
cluster. Overexpression
Overexpression of
of IL-20
IL-20 in
in transgenic
transgenic (TG)
(TG) mice
mice causes
causes neonatal
neonatal lethality
lethality
with
with skin
skin abnormalities
abnormalities including
including aberrant
aberrant epidermal
epidermal differentiation.
differentiation. Recombinant
Recombinant IL-20
IL-20
protein
protein stimulates
stimulates aa signal
signal transduction
transduction pathway
pathway through
through STAT3
STAT3 in
in aa keratinocyte
keratinocyte cell
cell line,
line,
demonstrating
demonstrating aa direct
direct action
action of
of this
this ligand.
ligand. An
An IL-20
IL-20 receptor
receptor was
was identified
identified as
as aa
heterodimer
heterodimer of
of two
two orphan
orphan class
class II
II cytokine
cytokine receptor
receptor subunits.
subunits. Both
Both receptor
receptor subunits
subunits are
are
expressed
expressed in
in skin
skin and
and are
are dramatically
dramatically upregulated
upregulated in
in psoriatic
psoriatic skin.
skin. Taken
Taken together,
together, these
these
results
results demonstrate
demonstrate aa role
role in
in epidermal
epidermal function
function and
and psoriasis
psoriasis for
for IL-20,
IL-20, aa novel
novel cytokine
cytokine
identified
identified solely
solely by
by bioinformatics
bioinformatics analysis.
analysis.
Immunol 2001 Oct 1;167(7):3545-9
Cutting edge: STAT activation by IL-19, IL-20 and mda-7 through IL20 receptor complexes of two types.
Dumoutier L, Leemans C, Lejeune D, Kotenko SV, Renauld JC
IL-10-related cytokines include IL-20 and IL-22, which induce,
respectively, keratinocyte proliferation and acute phase production by
hepatocytes, as well as IL-19, melanoma differentiation-associated gene
7, and AK155, three cytokines for which no activity nor receptor
complex has been described thus far.
Taken together, these results demonstrate that: 1) IL-20 induces STAT
activation through IL-20R complexes of two types; 2) mda-7 and IL-20
redundantly signal through both complexes; and 3) IL-19 signals only
through the type I IL-20R complex.
7
8
Immunity 2000 Nov;13(5):715-25
Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar
as well as distinct from IL-12.
Oppmann B, Lesley R, Blom B, Timans JC, Xu Y, Hunte B, Vega F, Yu N, Wang J, Singh K,
Zonin F, Vaisberg E, Churakova T, Liu M, Gorman D, Wagner J, Zurawski S, Liu Y, Abrams
JS, Moore KW, Rennick D, de Waal-Malefyt R, Hannum C, Bazan JF, Kastelein RA
DNAX Research Institute, Palo Alto, CA 94304, USA.
A novel sequence discovered in a computational screen appears distantly related to the p35
subunit of IL-12. This factor, which we term p19, shows no biological activity by itself; instead,
it combines with the p40 subunit of IL-12 to form a novel, biologically active, composite
cytokine, which we term IL-23. Activated dendritic cells secrete detectable levels of this
complex. IL-23 binds to IL-12R beta 1 but fails to engage IL-12R beta 2; nonetheless, IL-23
activates Stat4 in PHA blast T cells. IL-23 induces strong proliferation of mouse memory
(CD4(+)CD45Rb(low)) T cells, a unique activity of IL-23 as IL-12 has no effect on this cell
population. Similar to IL-12, human IL-23 stimulates IFN-gamma production and
proliferation in PHA blast T cells, as well as in CD45RO (memory) T cells.
9
J Biol Chem 2001 Nov 12;
Interleukin 24 (MDA-7/MOB-5) signals through two heterodimeric receptors,
IL-22R1/IL-20R2 and IL-20R1/IL-20R2.
Wang M, Tan Z, Zhang R, Kotenko SV, Liang P
Interleukin 24 (IL-24) encodes a secreted protein that exhibits significant
homology to the interleukin 10 (IL-10) family of cytokines. Here we show that
the human IL-24 is secreted by activated peripheral blood mononuclear cells
(PBMCs) and is the ligand for two heterodimeric receptors, IL-22R1/IL-20R2
and IL-20R1/IL-20R2. The latter is also the receptor for IL-20. Cos cells
transfected with either IL-24 receptor heterodimers bind the ligand with similar
saturation kinetics. IL-24 binding to either its endogenous receptors on human
keratinocytes or to ectopically expressed receptors on baby hamster kidney
(BHK) cells leads to activation of the signal transducers and activators of
transcription (STATs). Taken together, these results provide compelling
evidence for IL-24 being the fourth member of IL-10 family of cytokines to
which their specific receptors have been identified.
10
MO
Eta-1/Op
RGD
CD51-61
( αV-ß3)
• Reclutamiento celular
• Disminuye Sintasa de ON
• Regula remodelación tisular
“EL SWITH TH1- TH2 ES
UN PASO CRITICO QUE
DETERMINA LA
PROGRESION CLINICA
DE UNA ENFERMEDAD”
11
Balance Inmune
TH-1
TH-2
Disbalance Inmune Th1
TH-2
TH-1
IL-12
12
Disbalance Inmune Th2
IL-4 IL-10
TH-1
TH-2
Regulación Th1/Th2 x Treg
TH-2
TH-1
Treg
13