Primary role for Gi protein signaling in the regulation of interleukin 12 production and the induction of T helper cell type 1 responses.
We explored the role of Gi protein signaling in the regulation of interleukin (IL)-12 production and T helper cell type 1 (Th1) T cell differentiation. In initial studies, we showed that treatment of normal mice with pertussis toxin (PT), which inhibits Gi protein signaling, enhanced the capacity of splenocytes to produce IL-12 in response to both microbial and nonmicrobial stimuli. In addition, PT treatment increased the production of tumor necrosis factor (TNF)-alpha and IL-10 by stimulated cells. These findings were corroborated by the fact that untreated Gi2alpha(2/-) mice exhibited enhanced production of IL-12 and TNF-alpha by splenocytes, and of IL-12 p40 by purified spleen CD8alpha(+) lymphoid dendritic cells. Finally, we showed that while normal BALB/c mice infected with Leishmania major exhibited a nonhealing phenotype, those treated with PT when infection was initiated exhibited a healing phenotype along with an enhancement of leishmania-specific Th1 responses in draining lymph nodes. Further, healing was prevented by coadministration of anti-IL-12 and PT. These data demonstrate that endogenous Gi protein signaling has a primary role in the regulation of IL-12 production and the induction of Th1 responses in vivo.
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J
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Immune Cell Interaction Unit, Mucosal Immunity Section, Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Gurunathan
S
S
Iwasaki
A
A
Ash-Shaheed
B
B
Kelsall
B L
BL
D000246:Adenosine Diphosphate Ribose / Q000378:metabolism; D000818:Animals; D016827:CD8 Antigens; D002454:Cell Differentiation; D003713:Dendritic Cells / Q000276:immunology; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000235:genetics / Q000378:metabolism*; D007371:Interferon-gamma / Q000096:biosynthesis; D016753:Interleukin-10 / Q000096:biosynthesis; D018664:Interleukin-12 / Q000096:biosynthesis*; D015847:Interleukin-4 / Q000096:biosynthesis; D016773:Leishmaniasis, Cutaneous / Q000276:immunology; D008198:Lymph Nodes / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008817:Mice, Mutant Strains; D037342:Pertussis Toxin; D011499:Protein Processing, Post-Translational; D015398:Signal Transduction; D013154:Spleen / Q000166:cytology / Q000187:drug effects; D018417:Th1 Cells / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D016827:CD8 Antigens; D014409:Tumor Necrosis Factor-alpha; D010566:Virulence Factors, Bordetella; D016753:Interleukin-10; D018664:Interleukin-12; D015847:Interleukin-4; D000246:Adenosine Diphosphate Ribose; D007371:Interferon-gamma; D037342:Pertussis Toxin; D019206:GTP-Binding Protein alpha Subunits, Gi-Go