Autocrine regulation of IL-12 receptor expression is independent of secondary IFN-gamma secretion and not restricted to T and NK cells.
The biological response to IL-12 is mediated through specific binding to a high affinity receptor complex composed of at least two subunits (designated IL-12Rbeta1 and IL-12Rbeta2) that are expressed on NK cells and activated T cells. The selective loss of IL-12Rbeta2 expression during Th2 T cell differentiation suggests that regulation of this receptor component may govern IL-12 responsiveness. In murine assays, down-regulation of IL-12Rbeta2 expression can be prevented by treatment with IFN-gamma, indicating that receptor expression and hence IL-12 responsiveness may be regulated, at least in part, by the local cytokine milieu. In this study, we report that cellular expression of both IL-12Rbeta1 and beta2 mRNA is increased in the lymph nodes of naive mice following systemic administration of murine rIL-12 (rmIL-12). Changes in IL-12R mRNA were associated with increased IFN-gamma secretion following ex vivo activation of lymph node cells with rmIL-12, indicating the presence of a functional receptor complex. Expression of IL-12R mRNA was not restricted to lymph node T cells, and its autocrine regulation was independent of secondary IFN-gamma secretion. Data from fractionated lymph node cells as well as rmIL-12-treated B cell-deficient mice suggest that IL-12-responsive B cells may represent an alternative cellular source for IFN-gamma production. However, the strength of the biological response to rmIL-12 is not governed solely by receptor expression, as rmIL-12-induced IFN-gamma secretion from cultured lymph node cells is accessory cell dependent and can be partially blocked by inhibition of B7 costimulation.
Thibodeaux
D K
DK
Preclinical Research and Development, Genetics Institute, Andover, MA 01810, USA.
Hunter
S E
SE
Waldburger
K E
KE
Bliss
J L
JL
Trepicchio
W L
WL
Sypek
J P
JP
Dunussi-Joannopoulos
K
K
Goldman
S J
SJ
Leonard
J P
JP
D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology; D000938:Antigen-Presenting Cells / Q000276:immunology; D019898:Autocrine Communication / Q000276:immunology*; D018122:B7-1 Antigen / Q000276:immunology; D005260:Female; D007279:Injections, Subcutaneous; D007371:Interferon-gamma / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D018664:Interleukin-12 / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018123:Receptors, Interleukin / Q000096:biosynthesis* / Q000235:genetics; D053707:Receptors, Interleukin-12; D011994:Recombinant Proteins / Q000008:administration & dosage; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism
D019138:Antibodies, Blocking; D018122:B7-1 Antigen; C508443:Il12rb2 protein, mouse; D018123:Receptors, Interleukin; D053707:Receptors, Interleukin-12; D011994:Recombinant Proteins; D018664:Interleukin-12; D007371:Interferon-gamma