Primary role for Gi protein signaling in the regulation of interleukin 12 production and the induction of T helper cell type 1 responses

J Exp Med. 2000 May 1;191(9):1605-10. doi: 10.1084/jem.191.9.1605.


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.

MeSH terms

  • Adenosine Diphosphate Ribose / metabolism
  • Animals
  • CD8 Antigens
  • Cell Differentiation
  • Dendritic Cells / immunology
  • GTP-Binding Protein alpha Subunits, Gi-Go / genetics
  • GTP-Binding Protein alpha Subunits, Gi-Go / metabolism*
  • Interferon-gamma / biosynthesis
  • Interleukin-10 / biosynthesis
  • Interleukin-12 / biosynthesis*
  • Interleukin-4 / biosynthesis
  • Leishmaniasis, Cutaneous / immunology
  • Lymph Nodes / immunology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Mutant Strains
  • Pertussis Toxin
  • Protein Processing, Post-Translational
  • Signal Transduction
  • Spleen / cytology
  • Spleen / drug effects
  • Th1 Cells / immunology*
  • Tumor Necrosis Factor-alpha / biosynthesis
  • Virulence Factors, Bordetella / pharmacology


  • CD8 Antigens
  • Tumor Necrosis Factor-alpha
  • Virulence Factors, Bordetella
  • Interleukin-10
  • Interleukin-12
  • Interleukin-4
  • Adenosine Diphosphate Ribose
  • Interferon-gamma
  • Pertussis Toxin
  • GTP-Binding Protein alpha Subunits, Gi-Go