The role of heterodimers cytokines IL-12 family in development and regulation of innate immunity and Th1 immune response

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Abstract

IL-12 family consists from IL-12, IL-23 and IL-27 play crucial role in innate and adoptive immunity regu­lation. Herewith in spite of their structure homology they possess different sites in Th1 cells differentiation. So IL-27 is involved in Th1 cells development earlier than IL-12. It induces nanve T cells proliferation, activates of IL-12RP2 and T-bet expression. IL-23 plays role the key factor in T memory cells proliferation, defends them from apoptosis and increases their lifetime. IL-23 is a strong inducer of INF-y production.

Cytokines of IL-12 family participates in defense of organism from intracellular infection especially from tuberculosis. They induce antimycobacterial T cell immunity, develop tuberculomas, and activate CD8 cell to kill infected macrophages. In defense from infections are generated by T gondii and L. major IL-27 /WSX-1 are needed.

About the authors

S. A. Ketlinsky

SSC SRI Highly Pure Biopreparations

Author for correspondence.
Email: shabanov@mail.rcom.ru

член-корреспондент РАМН

Russian Federation, Saint Petersburg

References

  1. Abbas А.К., Murphy К.М., Sher A. Functional diversity Т lymphocytes //Nature. 1996. Vol. 383. P. 787-793.
  2. Agrawal S., Agrawal A., Doughty B. et al. Cutting edge: different Toll-like receptor agonists instruct dendritic cells to induce distinct Th responses via differential modulation of extracellular signal regulated kinase-mitogen-activated protein kinase and c-Fos // J. Immunol. 2003. Vol. 171. P. 4984-4989.
  3. Aggarwal S., Ghilardi N., Ming-Hong Xie et al. Interleukin-23 promotes a distinct CD4 T-cell activation state characterized by the production of IL-17 // J. Biol. Chem. 2003. Vol. 27 8. P. 1910-1914.
  4. Afkarian M., Sedy J.R., Yang J. et al. T-bet is a STATl-induced regulator of IL-12R expression in nanve CD4+ T-cells //Nature Immunol. 2002. Vol. 3. P. 549-558.
  5. Akira S. and Takeda K. Toll-like receptor signalling // Nature Rev. Immunol. 2004. Vol. 4. P. 499-511.
  6. Artis D., Johnson L.M., Joyce K. et al. Early IL-4 production governs the requirement for IL-27- WSX-1 signaling in development of protective Thl cytokine responses following Leishmania major infection // J. Immunol. 2004. Vol. 172. P. 4672-4675.
  7. Artis D., VUlarino A., Silverman M. et al. The IL-27 receptor (WSX-1) is an inhibitor of innate adaptive elements of type2 immunity // J. Immunol. 2004. Vol. 173. P. 5226-5234.
  8. Becker C., Wirtz S., Blessing M. et al. Consti¬tutive p40 promoter activation and IL-23 production in the terminal ileum mediated by dendritic cells//J. Clin. Invest. 2003. Vol. 112. P. 693-706.
  9. Belladonna M. L., Renauld J. C, Bianchi R. et al. IL-23 and IL-12 have overlapping, but distinct, effects on murine dendritic cells // J. Immunol. 2002. Vol. 168. P. 5448-5454.
  10. Beutler B. Interferences, questions and possibilities in Toll-like receptor signaling // Nature. 2004. Vol. 430. P. 257-271.
  11. Brombacher E, Kastelein R. A., Alber G. Novel IL-12 family members shed light on the orchestration of Thl responses // Trends in Immunol. 2003. Vol. 24. P. 207-212.
  12. Buxbaum L. U., Usonna J. E., Goldshmidt M. H., Scott R. Control of New World cutaneus lishmaniasis is IL-12 independent but STAT4 dependent // Eur. J. Immunol. 2002. Vol. 32. P. 3206-3215.
  13. Casatella M. A., Meda L., Gasperini S., D'And¬rea A., MaX., Trinchiery G. IL-12 production by human polymorphonuclear leukocytes // Eur. J. Immunol. 1995. Vol. 25. P. 251-255.
  14. Chakir H., Campos-Neto A., Mojibian M., Webb J. R. IL-12Rbeta-deficient mice of a genetically resistant background are susceptible to Leishmania major infection and develop a parasite-specific Th2 immune response // Microbes. Infect. 2003. Vol. 5. P. 241-249.
  15. Chen Q.f Ghilardi N., Wang H. et al. Develo¬ment of Thl-type immune responses requires the type 1 cytokine receptor TCCR // Nature. 2000. Vol. 407. P. 916-920.
  16. Chalifour A., Jeannin P, Gauchat J. E et al. Direct bacterial protein PAMP recognition by human NK cells involves TLRs and triggers alpha-defensin production // Blood. 2004. Vol. 104. P. 1778-1783.
  17. Chilardi N., Kljavin N., Chen Q. et al. Compromised humoral and delayed hypersensitivity responses in IL-23 deficient mice // J. Immunol. 2004. Vol. 172. P. 2827-2833.
  18. Cooper A. M., Kipnis A., Turner J. et al. Mice lacking bioactive IL-12 can generate protective, antigen specific cellular response to micobacterial infection only if the IL-12 p40 subunit is present//J. Immunol. 2002. Vol. 168. P. 1322-1327.
  19. Cooper A. M., Roberts A. D., Rhoades E. R. et al. The role of interleukin-12 in acquired immunity to micobacteria tuberculosis infection // Immunol. 1995. Vol. 84. P. 423-432.
  20. Debus A., Glasner J., Rollinghoff M., Gessner A. High levels of susceptibility and T helper 2 response in MyD88-deficient mice infected with Leishmania major are interleukin-4 dependent // Infect. Immunol. 2003. Vol. 71. P. 7215-7218
  21. Dillon S., Agrawal A., Van Dyke T. et al. A Toll-like receptor 2 ligand stimulates Th2 responses in vivo, via induction of extracellular signal-regulated kinase mitogen-activated protein kinase and e-Fos in dendritic cells // J. Immunol. 2004. Vol. 172. P. 473 3-4743.
  22. Doxsee C. L., Riter T, Reiter M. J. et al. The immune response modifier and TLR7 agonist S-27609 selectively induces IL-12 and TNF-a production in CDllc+ CDllb+CD8’ dendritic cells//J. Immunol. 2003. Vol. 171. P. 1156-1163.
  23. Elorido M., Concalves S., Gomes M. S, Appelberg R. CD40 is required for optimal induction of protective immunity to Mycobacterium avium // Immunol. 2004. Vol. 111. P. 323-327.
  24. Gat ley M. K. and Renzetti L. M., Magram J. et al. The interleukin-12/interleukin-12-receptor system: role in normal and pathologic immune responses//Annu. Rev. Immunol. 1998. Vol. 16. P. 495-521.
  25. Geros a E, Tomas si M., Benati C. et al. Differential effect of tyrosine kinase inhibition in CD69 antigen expression and lytic activity induced by IL-2, IL-12 and IFN-alpha in human NK cells H Cell. Immunol. 1993. Vol. 15 0. P. 3 82-3 90.
  26. Gubler U., Chua A. O., Schoenhaut D. S., Dwyer С. M. et al. Coexpression of two distinct genes is required to generate secreted bioactive cytotoxic lymphocyte maturation factor // Proc. Natl. Acad. Sci. 1991. Vol. 88. P. 4143-4147.
  27. Ha S. J, Kim D. J, Baek К H. et al. IL-23 induces stronger sustained CTL and Thl immune responses than IL-12 in hepatitis C virus envelope protein 2 DNA immunization // J. Immunol. 2004. Vol. 172. P. 525-531.
  28. Haltgren O.H., Verdrengh M., Tarkowski A. T-box transcription-factor-deficient mice display joint pathology and failure of infection control during staphylococcus arthritis // Microbes In¬fect. 2004. Vol. 6. P. 529-535.
  29. Hibbert L., Pflanz S., De Waal Malefyt R., Kastelein R. A. IL-27 and IFN-alpha signal via STAT1 and STAT3 in induce T-bet and IL-12RP2 in naive T-cells // J. Interferon Cytokine Res. 2003. Vol. 23. P. 513-522.
  30. Hickman S. P, Chan J., Salgame P. et al. M. tuberculosis induces differential cytokine production from dendritic cells and macrophages with divergent effects on nanve T cell polarization // J. Immunol. 2002. Vol. 168. P. 4636-4642.
  31. Janeway C. A. and Medzhitov R. Innate immune recognition // Annu. Rev. Immunol. 2002. Vol. 20. P. 197-216.
  32. Kal inski P, Storkus W. J., Thomson A. W., Lotze M. T Interleukin-12 family (IL-12,-23, 12RA, and -27): In The Cytokine Handbook. 4 ed. / Ed. by A. W. Tompson, M. T. Lotze. 2003. Vol. 1. P. 383-408.
  33. Kaplan M. H, San Y. I., Hoey T, and Grus by M. J. Impaired IL-12 responses and enhanced development of Th2 cells in STAT4-deficient mice // Nature. 1996. Vol. 3 82. P. 174-177.
  34. Kawakami K, Kinjo Y, Uezu К et al. Interferon-gamma production and host protective response against M. tubeculosis in mie lacking both IL-12p40 and IL-18 // Microbes Infect. 2004. Vol. 4. P. 339-349.
  35. Koguchi Y, Kawakami K, Uezu К et al. High osteopontin level and its relationship with IL-12 mediated type 1 T helper cell response in tuberculosis // Am. J. Respir. Crit. Care Med. 2003. Vol. 167. P. 13 5 5-13 59.
  36. Krug A., Towarowski A., Britsch S. etal. Toll-like receptor expression reveals CpG DNA as a unique microbial stimulus for plasmacytoid dendritic cells which synergizes with CD40 ligand to induce high amounts IL 12 // Eur. J. Immunol. 2001. Vol. 31. P. 3 7692-3 7699.
  37. Kubin M., Kamoun M., Trinchiery G. IL-12 synergizes with B7/CD28 interaction in inducing efficient proliferation and cytokine production of human T cells // J. Exp. Med. 1994. Vol. 180. P. 211-222.
  38. Larousserie E, Pflanz S., Colomb-LHermine A. et al. Expression of IL-27 in human Thl-associated granulomatous diseases // J. Pathol. 2004. Vol. 202. P. 164-171.
  39. Lazarevic V., Myers A. J., Scanga C. A., Flynn J. L. CD-40, but not CD40L, Is required for the optimal IL-27 priming of T cells and control of aerosol M. tuberculosis infection // Immunity. 2003. Vol. 19. P. 823-83 5.
  40. Lee E., Trepicchio W. L., Ostreicher J. L. et al. Increased expression of interleukin 23pl9 and p40 in lesional skin of patients with psoriasis vulgaris // J. Exp. Med. 2004. Vol. 199. P. 125-13 0.
  41. Lemaitre B., Nicolas E., Michaut L. et al. The dorsoventral regulatory gene cassette spatzle /toll/cactus controls the potent antifungal response in Drosophila adults // Cell. 1996. Vol. 86. P. 973-983.
  42. Leung D. Y M., Gately M., Tramble A. Fergusson-Darnell B. et al. Bacterial superantigenes induce T-cell expression of the skin-selective homing receptor, the cutaneous lymphocyte-associated antigen via stimulation of IL-12 production // J. Exp. Med. 1995. Vol. 181. P. 747-753.
  43. Li J., Gran B., Zhang G. X. Ventura E. S. et al. Differential expression and regulation of IL-23 and IL-12 subunits and receptors in adult mouse microglia // J. Neurol. Sci. 2003. Vol. 215. P. 95-103.
  44. Lieberman L. A., Banica V, Reiner S. L., Hanter C. A. STAT1 plays a critical role in the regulation of antimicrobial effector mechanisms, but not in the development of Thl-type responses during toxoplasmosis I/ J. Immunol. 2004. Vol. 172. P. 457-463.
  45. Lighvani A., Frucht D.M., Jancovich D.f Yamane H et al. T-bet is rapidly induced by interferon-y in lymphoid and myeloid cells // Proc. Natl. Acad. Sci. USA. 2001. Vol. 9 8. P. 1513 7-15142.
  46. Lucas S., Ghilardi N., Li J., DeSauvage E J. IL-27 regulates IL-12 responsiveness of nanve CD4+ T-cells through STAT1 dependent and independent mechanisms // Proc. Natl. Acad. Sci. USA. 2003. Vol. 100. P. 15047-15052.
  47. Matsui M., Moriya O., Beladonna M. L. et al. Adjuvant activities of novel cytokines, IL-23 and IL-27 for induction of hepatitis C virus specific cytotoxic T lymphocytes in HLA-A 0201 transgenic mice H J. Virol. 2004. Vol. 78. P. 9093-9104.
  48. Medzhitov R. and Janeway A. C. Innate immunity: the virtues of a nonclonal system of recognition // Cell. 1997. Vol. 91. P. 295-298.
  49. Morinobu A., GadinaM., Strober W. et al. STAT4 serine phosphorylation is critical for IL-12-induced IFN-y production but not for cell proliferation // Proc. Natl. Acad. Sci. 2002. Vol. 99. P. 1281-1286.
  50. Mossmann T R., Coffman R. L. Two types of mouse helper T-cell clone: implication for immune regulation // Immunol. Today. 1987. Vol. 8. P. 223-227.
  51. Mossmann T. R., Coffman R. L. Thl and Th2 cells different patterns of lymphokine-secretion lead to different functional properties // Ann. Rev. Immunol. 1989. Vol. 7. P. 147-173.
  52. Mullen A., High E A., Hutchins A. S. et al. Role of T-bet in commitment of Thl cells before IL-12-dependent selection // Science. 2001. Vol. 292. P. 1907-1910.
  53. Murphy E.E., Terres G., Macontonia S.E., Hsieh C. S. et al. B7 and IL-12 cooperate for proliferation and IFN-gamma production by mouse Т helper clones that are unresponsive to B7 costimulation // J. Exp. Med. 1994. Vol. 180. P. 211-222.
  54. Naume B., Gately M., Espevik T A. A. comparative study of IL-12, IL-2 and IL-7-induced effect on immunomagnetically purified CD-56+ NK cells // J. Immunol. 1992. Vol. 148. P. 2429-243 6.
  55. Nigon J., Zelle-Rieser C.t Gilleron M. et al. Mannosylated lipoarabinomannans inhibit IL-12 prodution by human dendritic cells: evidence for a negative signal delivered through the mannose receptor // J. Immunol. 2001. Vol. 166. P. 7477-7485.
  56. Nishikomori R., Usui T, Wu C-Y, Morinobu A., O'Shea J. J., Strober W. Activated STAT4 has a essential role in Thl differentiation and proliferation that is independent of its role in the maintenance ofILRp2 chain expression and signaling // J. Immunol. 2002. Vol. 169. P. 43 8 8-443 9.
  57. Nguen К. B., Watford W T, Salomon R. et al. Critical role for STAT4 activation by type 1 interferons in the interferon-gamma response to viral infection // Science. 2002. Vol. 297. P. 2063-2066.
  58. Nolt D., Flynn J. L IL-12 therapy reduces the number of immune cells and pathology in lungs of mice infected with Micobacterium tuberculosis // Infect. Immun. 2004. Vol. 72. P. 2976-29 8 8.
  59. Oppmann B., Lesley R., Blom B. Novel pl9 pro¬tein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12 // Immunity. 2000. Vol. 13. P. 715-725.
  60. Parham C., Chirica M., Timans J. et al. A receptor for the heterodimeric cytokine IL-23 is com¬posed of IL-12Rpl and novel cytokine receptor subunit, IL-23 R // J. Immunol. 2002. Vol. 168. P. 5699-5708.
  61. Pearce E. L., Mullen A. C., Martins G. A. Control of effector CD8+ T-cell function by the transctiption factor Eomesodermin // Science. 2003. Vol. 3 02. P. 993-994.
  62. PirhonenJ., Matikinen S., Julkunen I. Regulation of virus-induced IL-12 and IL-23 expression in human macrophages // J. Immunol. 2002. Vol. 169. P. 5 673-5 67 8.
  63. Pflanz S., Hibbert L., Mattson J. et al. WSX-1 and glycoprotein 130 constitute a signal-transducing receptor for IL-27 // J. Immunol. 2004. Vol. 172. P. 2225-2231.
  64. Pflanz S., Timans J.C., Cheung J. et al. IL-27, a heterodimeric cytokine composed of EBI3 and p28 protein, induces proliferation of nanve CD4+ T cells // Immunity. 2002. Vol. 16. P. 779-790.
  65. Poltarak A., He X., Smirnova I. et al. Defective LPS signaling C3H/HeJ and C57BL/10ScCr mice; mutation in Tlr gene // Science. 1998. Vol. 282. P. 2085-2088.
  66. Presky D. H, Minetti L. J., Gillessen S. et al. Evidence for multiple sites of interaction between IL-12 and its receptor // Ann. NY Acad. Sci. 1996. Vol. 795. P. 390-393.
  67. Presky D. H, Yang H, Minetti L. J. et al. A func¬tional IL-12 receptor complex is composed of two beta-type cytokine receptor subunits // Proc. Natl. Acad. Sci. USA. 1996. Vol. 93. P. 14002-14007.
  68. Robertson M. J., Soiffer R. J., Wolf S. F et al. Responses of human natural killer cells to NK stimulating factor (NKSF). Cytolytic activity and proliferation of NK cells are differently regulated by NKSF // J. Exp. Med. 1992. Vol. 175. P. 779-788.
  69. Samten B., Wizel B.f Shams H CD40 ligand trimer enhances the response of CD8+ T-cells to M. tuberculosis // J. Immunol. 2003. Vol. 170. P. 3180-3186.
  70. Shiina M., Kobayashi K, Satoh H. et al. Ribavirin upregulates IL-12 receptor and induces T-cell differentiation towards tipel in chronic hepatitis C // J. Gastroenterol. Hepatol. 2004. Vol. 19. P. 558-564.
  71. Shilling D., Thomas K, Nixdorff К et al. Toll-like receptor 4 and Toll-IL-1 receptor domain-containing adaptor protein (TIRAP)/myeloid differentiation protein 88 adaptor-like (Mal) contribute to maximal IL-6 expression in macrophages // J. Immunol. 2002. Vol. 169. P. 5 874-5780.
  72. Smits HH, Van Beelen A.J., Hessle C. et al. Commensal Gram-negative bacteria prime human dendritic cells for enhanced IL-23 and IL-27 expression and enhanced Thl development // Eur. J. Immunol. 2004. Vol. 34. P. 1371-1380.
  73. Song C., Kim H J., Park J. К et al. Depressed IL-12, but not IL-18, production in response to a 30-35 kilodalton micobacterial antigen in patients with acute pulmonary tuberculosis // Infect. Immunol. 2000. Vol. 68. P. 4477-4484.
  74. Sprecher C.A., Grant FJ., Baumgartner J.W Cloning and characterization of a novel class 1 cytokine receptor // Bichem. Biophys. Res. Commun. 1998. Vol. 8. P. 82-90.
  75. Sugawara L, Yamada H, Mizuno S. STAT1 knockout mice are highly susceptible to pulmonary mycobacterial infection // Tohoku J. Exp. Med. 2004. Vol. 202. P. 41-5 0.
  76. Szabo S. J., Dighe A. S., Gubler U, Murphy К M. Regulation of the interleukin-12RP2 subunit expression in developing T helper 1 (Thl) and Th2 cells // J. Exp. Med. 1987. Vol. 185. P. 817-824.
  77. Szabo S. J., Kim S. T., Costa G. Z., Zhang X. et al. A novel transcription factor, T-bet, directs Thl lineage commitment // Cell. 2000. Vol. 100. P. 655-669.
  78. Takeda A., Hamano S., Yamanaka A. Role of IL-27/WSX-1 signaling for induction of T-bet through activation of STAT1 during initial Thl commitment // J. Immunol. 2003. Vol. 170. P. 4886-4890.
  79. Tekkanat К. K, Maassab H., Berlin A. et al. Role of IL-12 and STAT4 in the regulation of airway inflammation and hyperreactivity in respiratory syncytial virus infection // Am. J. Pathol. 2001. Vol. 159. P. 631-63 8.
  80. Thierfelder WE., van Deursen J.M., Yamomoto К et al. Requirement for STAT4 in interleukin-12-mediated responses of natural killer and T-cells // Nature. 1996. Vol. 382. P. 171-174.
  81. Townsend M. J., Weinmann A. S., Matsuda J. L. et al. T-bet regulates the terminal maturation and homeostasis of NK and Valphal4i NKT cells // Immunity. 2004. Vol. 20. P. 477-494.
  82. Toyoda H, Ido M., Hayashi T et al. Impairment of IL-12-dependent STAT4 nuclear translocation in a patient with recurrent Micobacterium avium infection // J. Immunol. 2004. Vol. 172. P. 3905-3912.
  83. Trinchiery G. Interleukin-12 and the regulation of innate resistance and adaptive immunity // Nature Rev. Immunol. 2003. Vol. 3. P. 133-148.
  84. Trinchiery G. Interleukin-12: a cytokine at the interface of inflammation and immunity // Adv. Immunol. 1993. Vol. 70. P. 183-243.
  85. Trinchiery G., Pflanz S., Kas telein R. The IL-12 family of heterodimeric cytokines: new players in the regulation of T-cell response // Immunity. 2003. Vol. 19. P. 641-644.
  86. Tripp C. S., WolfS. E, Unanue E. R. Interleukin-12 and TNF-a are costimulators of INF-y production by natural killer cells in severe combined immunodeficiency mice with listeriosis and IL-10 is a physiologic antagonist // Proc. Natl. Acad. Sci. USA. 1993. Vol. 90. P. 3725-3 729.
  87. Tripp C. S., Gately M. K, Hakimi J. et al. Neutralization of IL-12 decreases resistance to Listeria in SCID and C.B-17 mice. Reversal by IFN-gamma // J. Immunol. 1994. Vol. 152. P. 1883-1887.
  88. Vanderbroeck K, A Hoza L, Gadina M., Matt- hys P. Inhibiting cytokines of the IL-12 family: recent advances and novel challenges // J. Pharm. Pharmacol. 2004. Vol. 56. P. 145-160.
  89. VerreckF. A., De Boer T, Langenberg D. M. et al. Human IL-23-producing type 1 macrophages promote but IL-10-producing type 2 sub¬vert immunity to (mico)bacteria // Proc. Natl. Acad. Sci. USA. 2004. Vol. 101. P. 4560-4565.
  90. Villarino A., Hibbert L., Lieberman L. et al. The IL-27R(WSX-1) is required to suppress T-cell hyperactivity during infection // Immunity. 2003. Vol. 19. P. 645-655.
  91. Villarino A., Heang E., Hunter C. A. Understanding the pro- and anti-inflammatory properties of 27 // J. Immunol. 2004. Vol. 173. P. 715-720.
  92. Wesa A. and Gaily A. Increased production of pro-inflammatory cytokines and enchanced T cell responses after activation of human dendritic cells with IL-1 and ligand // BMC Immunol. 2002. Vol. 3. P. 14.
  93. Wiekowski M. T, Leach M. W, Evans E.W et al. Ubiquitous transgenic expression of the IL-23 subunit pl9 induces multiorgan inflammation, runting, unfertility, and premature death // J. Immunol. 2001. Vol. 166. P. 7563-7570.
  94. Wu C.-Y, Demeure C., Kiniwa M., Gately M., Delespesse G. IL-12 induces the production of IFN-gamma by neonatal human CD4 T-cells // J. Immunol. 1993. Vol. 151. P. 193 8-1949.
  95. Wu C.-Y, Wang X, Presky D.H., and Mag¬ram J. IL-12 receptor beta 2 (IL-12Rp2)-deficient mice bind IL-12 but are deficient in IL-12-mediated responses // FASEB J. 2000. Vol. 14. P. 1083-1090.
  96. Yoshida H, Hamano S., Senaldi G., Covey T et al. WSX-1 is required for the initiation of Thl responses and resistance to L. major infection // Immunity. 2001. Vol. 15. P. 569-578.
  97. Yoshimoto T, Wang C.R, Yoneto T et al. Reduced IL-12 T helper 1 responses in IL12p40 transgenic mice // J. Immunol. 1998. Vol. 160. P. 5 8 8-594.
  98. Zhang E., Nakamura T, and Aune T M. TCR and IL-12 receptor signals cooperate to activate an individual response element in the IFN-y promoter in effector Thl cells // J. Immunol. 1999. Vol. 163. P. 728-73 5.
  99. Zhang M., Gately M.K., Wang E., Gong J. et al. IL-12 at the site of disease in tuberculosis // J. Clin. Invest. 1994. Vol. 93. P. 173 3-173 8.
  100. Zou J., Presky D.H, Wu C.Y, and Gubler U. Differential associations between the cytoplasmic regions of the interleukin-12 receptor subunits betal and beta2 and JAK kinases // J. Biol. Chern. 1997. Vol. 272. P. 6073-6077.

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