Negative feedback on IL-23 exerted by IL-17A during pulmonary inflammation

Innate Immun. 2013 Oct;19(5):479-92. doi: 10.1177/1753425912470470. Epub 2013 Jan 7.


It is now established that IL-17 has a broad pro-inflammatory potential in mammalian host defense, in inflammatory disease and in autoimmunity, whereas little is known about its anti-inflammatory potential and inhibitory feedback mechanisms. Here, we examined whether IL-17A can inhibit the extracellular release of IL-23 protein, the upstream regulator of IL-17A producing lymphocyte subsets, that is released from macrophages during pulmonary inflammation. We characterized the effect of IL-17A on IL-23 release in several models of pulmonary inflammation, evaluated the presence of IL-17 receptor A (RA) and C (RC) on human alveolar macrophages and assessed the role of the Rho family GTPase Rac1 as a mediator of the effect of IL-17A on the release of IL-23 protein. In a model of sepsis-induced pneumonia, intravenous exposure to Staphylococcus aureus caused higher IL-23 protein concentrations in cell-free bronchoalveolar lavage (BAL) samples from IL-17A knockout (KO) mice, compared with wild type (WT) control mice. In a model of Gram-negative airway infection, pre-treatment with a neutralizing anti-IL-17A Ab and subsequent intranasal (i.n.) exposure to LPS caused higher IL-23 and IL-17A protein concentrations in BAL samples compared with mice exposed to LPS, but pre-treated with an isotype control Ab. Moreover, i.n. exposure with IL-17A protein per se decreased IL- 23 protein concentrations in BAL samples. We detected IL-17RA and IL-17RC on human alveolar macrophages, and found that in vitro stimulation of these cells with IL-17A protein, after exposure to LPS, decreased IL-23 protein in conditioned medium, but not IL-23 p19 or p40 mRNA. This study indicates that IL-17A can partially inhibit the release of IL-23 protein during pulmonary inflammation, presumably by stimulating the here demonstrated receptor units IL-17RA and IL-17RC on alveolar macrophages. Hypothetically, the demonstrated mechanism may serve as negative feedback to protect from excessive IL-17A signaling and to control antibacterial host defense once it is activated.

Keywords: IL-17; IL-23; Rac1; airway inflammation; bronchoalveolar lavage; host defense; human; macrophages; mouse; neutrophils.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Blocking / administration & dosage
  • Cells, Cultured
  • Feedback, Physiological / drug effects
  • Interleukin-17 / administration & dosage
  • Interleukin-17 / genetics
  • Interleukin-17 / immunology*
  • Interleukin-23 / genetics
  • Interleukin-23 / immunology
  • Interleukin-23 / metabolism*
  • Lipopolysaccharides / immunology
  • Macrophages, Alveolar / drug effects
  • Macrophages, Alveolar / immunology
  • Macrophages, Alveolar / metabolism*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Pneumonia / etiology
  • Pneumonia / immunology*
  • Receptors, Interleukin / metabolism
  • Receptors, Interleukin-17 / metabolism
  • Staphylococcal Infections / complications
  • Staphylococcal Infections / immunology*
  • Staphylococcus aureus / immunology*
  • rac1 GTP-Binding Protein / metabolism


  • Antibodies, Blocking
  • IL17RA protein, human
  • IL17RC protein, human
  • Interleukin-17
  • Interleukin-23
  • Lipopolysaccharides
  • RAC1 protein, human
  • Receptors, Interleukin
  • Receptors, Interleukin-17
  • rac1 GTP-Binding Protein