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Las Citocinas (III)Las Citocinas (III)

Dr. Juan Rodríguez-Tafur D.Profesor Asociado de Farmacología e Inmunología

Laboratorio de Farmacología de la Respuesta InmuneCoordinador del Comité de Residentado Médico de

Inmunología Clinica y AlergologíaFacultad de Medicina – UNMSM

Lima (Perú)

Dr. Juan Rodríguez-Tafur D.Profesor Asociado de Farmacología e Inmunología

Laboratorio de Farmacología de la Respuesta InmuneCoordinador del Comité de Residentado Médico de

Inmunología Clinica y AlergologíaFacultad de Medicina – UNMSM

Lima (Perú)

Agosto 2005

OTRAS CITOQUINASOTRAS CITOQUINAS

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INTERLEUQUINA-7 (IL-7)

GLICOPROTEINA DE 25 KD

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

MITOGENO (CON SCF) DE TIMOCITOS Y CEL PRE-B

MEJORA LA FUNCION DE CEL. CITOTOXICAS

DEFICIT EN ANIMALES PRODUCE HIPOPLASIA LINFOIDE DE CELULAS T Y B.

INTERLEUQUINA-7 (IL-7)

GLICOPROTEINA DE 25 KD

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

MITOGENO (CON SCF) DE TIMOCITOS Y CEL PRE-B

MEJORA LA FUNCION DE CEL. CITOTOXICAS

DEFICIT EN ANIMALES PRODUCE HIPOPLASIA LINFOIDE DE CELULAS T Y B.

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PROTEINA DE 19 KD

ACTUA COMO FACTOR DE CRECIMIENTO DE CELULAS BLASTICAS

SINERGISMO CON IL-3, IL-4, CSF-GM

ROL IMPORTANTE EL HEMATOPOIESIS, LINFOPOIESIS, DESARROLLO DE ADIPOCITOS,NEURONAS Y OSTEOCLASTOS

CON IL-3 INCREMENTAN EL NUMERO Y TAMAÑO DE LAS COLONIAS DE MEGACARIOCITOS

PROTEINA DE 19 KD

ACTUA COMO FACTOR DE CRECIMIENTO DE CELULAS BLASTICAS

SINERGISMO CON IL-3, IL-4, CSF-GM

ROL IMPORTANTE EL HEMATOPOIESIS, LINFOPOIESIS, DESARROLLO DE ADIPOCITOS,NEURONAS Y OSTEOCLASTOS

CON IL-3 INCREMENTAN EL NUMERO Y TAMAÑO DE LAS COLONIAS DE MEGACARIOCITOS

Nordan RP, Potter M Science 233(4763):566-9 (1986)Paul SR y col. Proc. Natl. Acad. Sci. USA 87:7512 (1990)Nordan RP, Potter M Science 233(4763):566-9 (1986)Paul SR y col. Proc. Natl. Acad. Sci. USA 87:7512 (1990)

HETERODIMERO DE 2 SUBUNIDADES DE 35 Y 40 KD

LA PRODUCC. DE IL-12 ES ACTV. POR MACROFAGOSY ES INHIBIDO POR IL-4 Y POR IL-10

INDUCE PRODUCCION DE IFN-γ, PROMUEVE LA PROLIF. DE CEL T ACTV. Y CEL. NKINDUCE TH-O A TH-1 SUPRIME TH-2 INDUCE PRODUCION DE CSF-GM, TNF, IL-6 , EN MENOR PROPORCION IL-2 (ACCION SINERGICA CON IL-2)

HETERODIMERO DE 2 SUBUNIDADES DE 35 Y 40 KD

LA PRODUCC. DE IL-12 ES ACTV. POR MACROFAGOSY ES INHIBIDO POR IL-4 Y POR IL-10

INDUCE PRODUCCION DE IFN-γ, PROMUEVE LA PROLIF. DE CEL T ACTV. Y CEL. NKINDUCE TH-O A TH-1 SUPRIME TH-2 INDUCE PRODUCION DE CSF-GM, TNF, IL-6 , EN MENOR PROPORCION IL-2 (ACCION SINERGICA CON IL-2)

Gately y col. J. Immunol. 136,1274-1281 (1986)Wong y col. Cell Immunol. 111,39-54 (1987)

Gately y col. J. Immunol. 136,1274-1281 (1986)Wong y col. Cell Immunol. 111,39-54 (1987)

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GLICOPROTEINA DE 50-60 KD ANTES CONOCIDO COMO FACT. DE CRECIMIENTO DE CELULAS B DE ALTO PESO MOLECULAR ES PRODUCIDA POR CEL. DENDRITICAS FOLICULARES Y CELULAS T ES MITOGENO DE CELULAS B ACTIVADAS

GLICOPROTEINA DE 50-60 KD ANTES CONOCIDO COMO FACT. DE CRECIMIENTO DE CELULAS B DE ALTO PESO MOLECULAR ES PRODUCIDA POR CEL. DENDRITICAS FOLICULARES Y CELULAS T ES MITOGENO DE CELULAS B ACTIVADAS

Pre - BPre - B

BBmemoriamemoria

TT IL-14IL-14

Ambrus,J.L. and Fauci,A.S. J. Clin. Invest. 75,732-739 (1985)Ambrus,J.L. and Fauci,A.S. J. Clin. Invest. 75,732-739 (1985)

Céls dendríticasfolicularesCéls dendríticasfoliculares

INTERLEUQUINA-15 (IL-15)

PRODUCIDO POR CEL. EPITELIALES Y MONOCITOSPERO NO POR LINFOCITOS T

INDUCE PROLIF DE CEL T ACTIVAS

GENERA CEL T CITOTOXICAS ESPECIFICAS

SE EXPRESA EN PLACENTA, MUSC. ESQUEL, RINON, PULMON, HIGADO, CORAZON Y ESTROMA DE M.O.

IL-2, IL-4, IL-7, IL-9, IL-15 COMPATEN EL RECEPTOR(IL-2Rγ, SU DEFICIENCIA PRODUCE X-SCID)

INTERLEUQUINA-15 (IL-15)

PRODUCIDO POR CEL. EPITELIALES Y MONOCITOSPERO NO POR LINFOCITOS T

INDUCE PROLIF DE CEL T ACTIVAS

GENERA CEL T CITOTOXICAS ESPECIFICAS

SE EXPRESA EN PLACENTA, MUSC. ESQUEL, RINON, PULMON, HIGADO, CORAZON Y ESTROMA DE M.O.

IL-2, IL-4, IL-7, IL-9, IL-15 COMPATEN EL RECEPTOR(IL-2Rγ, SU DEFICIENCIA PRODUCE X-SCID)

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CD8+CD8+ IL-16IL-16

CD4+CD4+

SUPRIMEINFECCIONSUPRIMESUPRIMEINFECCIONINFECCION

HIVHIVHIV

Kurth, R. Nature Dec 1995.KurthKurth, R. , R. NatureNature DecDec 1995.1995.

CONOCIDO ANTES COMO LCF (FACTOR QUIMIO-ATRAYENTE DE LINFOCITOS)

INDUCE LA MIGRACION DIRECCIONAL DE CD4+, EOSINOFILOS Y MONOCITOS

↑ IL-2Rα ↑ CMH-II EN CELULAS T

CONOCIDO ANTES COMO LCF (FACTOR QUIMIO-ATRAYENTE DE LINFOCITOS)

INDUCE LA MIGRACION DIRECCIONAL DE CD4+, EOSINOFILOS Y MONOCITOS

↑ IL-2Rα ↑ CMH-II EN CELULAS T

IL-17 (cytotoxic T-lymphocyte-associated antigen-8 CTLA-8)

Estímulo

Célula T

Fibroblasto

PRODUCIDA POR CELULAS T

ACTIVA AL FACTOR DE TRANSDUCCION NF-κBINDUCE LA EXPRESION DE VARIAS CITOQUINASPROINFLAMATORIAS Y DE ICAM-1

ACTUA SOBRE RECEPTORES DE UNA GRAN VARIEDAD DE CELULAS

PRODUCIDA POR CELULAS T

ACTIVA AL FACTOR DE TRANSDUCCION NF-κBINDUCE LA EXPRESION DE VARIAS CITOQUINASPROINFLAMATORIAS Y DE ICAM-1

ACTUA SOBRE RECEPTORES DE UNA GRAN VARIEDAD DE CELULAS

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Apoptosis de Célulasque expresan FAS

Antígeno

Antígeno

Activación deMacrófagos

INTERLEUQUINA-18 (IL-18)

PROTEINA DE 17 KD

PRODUCIDA POR CEL T ACTIVAS, ACTIVA CEL T Y ACTUA SOBRE MUCHAS OTRAS CEL COMO PRO-INFLAMATORIA

TAMBIEN DENOMINADA FACTOR INDUCTOR DE IFN-γ.

ESTRUCTURA SIMILAR A IL-1α, IL-1β E IL-1RA SE PROPOSO DENOMINARLA IL-1γ

INDUCE IFN- γ E INHIBE IL-10. FUNCION SIMILAR Y SINERGICA CON IL-12

INTERLEUQUINA-18 (IL-18)

PROTEINA DE 17 KD

PRODUCIDA POR CEL T ACTIVAS, ACTIVA CEL T Y ACTUA SOBRE MUCHAS OTRAS CEL COMO PRO-INFLAMATORIA

TAMBIEN DENOMINADA FACTOR INDUCTOR DE IFN-γ.

ESTRUCTURA SIMILAR A IL-1α, IL-1β E IL-1RA SE PROPOSO DENOMINARLA IL-1γ

INDUCE IFN- γ E INHIBE IL-10. FUNCION SIMILAR Y SINERGICA CON IL-12

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Cell 2001 Jan 12;104(1):9-19

Interleukin 20: discovery, receptor identification, and role in epidermal function.

Blumberg H, Conklin D, Xu WF, Grossmann A, Brender T, Carollo S, Eagan M, Foster D, Haldeman BA, Hammond A, Haugen H, Jelinek L, Kelly JD, Madden K, Maurer MF, Parrish-Novak J, Prunkard D, Sexson S, Sprecher C, Waggie K, West J, Whitmore TE, Yao L, Kuechle MK, Dale BA, Chandrasekher YA

Department of Genetics, ZymoGenetics, Inc., 1201 Eastlake Avenue E, Seattle, WA 98102, USA.

A structural, profile-based algorithm was used to identify interleukin 20 (IL-20), a novel IL-10 homolog. Chromosomal localization of IL-20 led to the discovery of an IL-10 family cytokine cluster. Overexpression of IL-20 in transgenic (TG) mice causes neonatal lethality with skin abnormalities including aberrant epidermal differentiation. Recombinant IL-20 protein stimulates a signal transduction pathway through STAT3 in a keratinocyte cell line, demonstrating a direct action of this ligand. An IL-20 receptor was identified as a heterodimer of two orphan class II cytokine receptor subunits. Both receptor subunits are expressed in skin and are dramatically upregulated in psoriatic skin. Taken together, these results demonstrate a role in epidermal function and psoriasis for IL-20, a novel cytokine identified solely by bioinformatics analysis.

Cell 2001 Jan 12;104(1):9-19

Interleukin 20: discovery, receptor identification, and role in epidermal function.

Blumberg H, Conklin D, Xu WF, Grossmann A, Brender T, Carollo S, Eagan M, Foster D, Haldeman BA, Hammond A, Haugen H, Jelinek L, Kelly JD, Madden K, Maurer MF, Parrish-Novak J, Prunkard D, Sexson S, Sprecher C, Waggie K, West J, Whitmore TE, Yao L, Kuechle MK, Dale BA, Chandrasekher YA

Department of Genetics, ZymoGenetics, Inc., 1201 Eastlake Avenue E, Seattle, WA 98102, USA.

A structural, profile-based algorithm was used to identify interleukin 20 (IL-20), a novel IL-10 homolog. Chromosomal localization of IL-20 led to the discovery of an IL-10 family cytokine cluster. Overexpression of IL-20 in transgenic (TG) mice causes neonatal lethality with skin abnormalities including aberrant epidermal differentiation. Recombinant IL-20 protein stimulates a signal transduction pathway through STAT3 in a keratinocyte cell line, demonstrating a direct action of this ligand. An IL-20 receptor was identified as a heterodimer of two orphan class II cytokine receptor subunits. Both receptor subunits are expressed in skin and are dramatically upregulated in psoriatic skin. Taken together, these results demonstrate a role in epidermal function and psoriasis for IL-20, a novel cytokine identified solely by bioinformatics analysis.

Immunol 2001 Oct 1;167(7):3545-9

Cutting edge: STAT activation by IL-19, IL-20 and mda-7 through IL-20 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 receptorcomplex 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.

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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.

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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.

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Eta-1/OpEta-1/OpMO

CD51-61( αV-ß3)CD51-61( αV-ß3)

RGDRGD

• 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”

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Balance Inmune

TH-1 TH-2

TH-2

TH-1

IL-12

Disbalance Inmune Th1

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Disbalance Inmune Th2

TH-2

TH-1IL-4 IL-10

TH-1

TH-2

Treg

Regulación Th1/Th2 x Treg