Higher TNFα responses in young males compared to females are associated with attenuation of monocyte adenylyl cyclase expression

Hum Immunol. 2015 Jun;76(6):427-30. doi: 10.1016/j.humimm.2015.03.018. Epub 2015 May 7.


Tumor necrosis factor α (TNFα) expression is strongly attenuated by the intracellular signaling mediator cyclic adenosine monophosphate (cAMP), which is synthesized by adenylyl cyclase (AC) enzymes. We have compared AC regulation and TNFα production in male and female monocytes, and characterized the role of monocyte AC isoforms in TNFα regulation. Males and females, age groups 20-30 years and 50-70 years donated blood for this study. In lipopolysaccharide-stimulated blood from young male donors, we observed significantly higher TNFα responses (6h, p=0.03) compared to females of the same age, a difference not observed in the older donors. Rapid down-regulation of the monocyte AC isoforms AC4, AC7 and AC9 were observed in young males. AC-directed siRNA experiments in the human monocyte cell line THP-1 demonstrated that AC7 and AC9 knock-down significantly induced TNFα release (p=0.01 for both isoforms). These data indicate that the stronger TNFα-responses in young males may be partly associated with male-specific down-regulation of adenylyl cyclases.

Keywords: Adenylyl cyclase; Gender; Lipopolysaccharide; Monocytes; Tumor necrosis factor alpha.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenylyl Cyclases / genetics*
  • Adenylyl Cyclases / immunology
  • Adult
  • Aged
  • Cell Line
  • Cyclic AMP / metabolism
  • Female
  • Gene Expression Regulation
  • Humans
  • Lipopolysaccharides / pharmacology
  • Male
  • Middle Aged
  • Monocytes / cytology
  • Monocytes / drug effects
  • Monocytes / immunology*
  • Primary Cell Culture
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Signal Transduction
  • Tumor Necrosis Factor-alpha / biosynthesis*
  • Tumor Necrosis Factor-alpha / immunology


  • Lipopolysaccharides
  • RNA, Small Interfering
  • Tumor Necrosis Factor-alpha
  • Cyclic AMP
  • Adenylyl Cyclases
  • adenylate cyclase 9
  • adenylyl cyclase 4
  • adenylyl cyclase 7