IL12p40 regulates functional development of human CD4+ T cells: enlightenment by the elevated expressions of IL12p40 in patients with inflammatory bowel diseases

Medicine (Baltimore). 2015 Mar;94(10):e613. doi: 10.1097/MD.0000000000000613.

Abstract

The proinflammatory effects of IL12p40 had been documented in the literature, and anti-IL12p40 treatment had been proved to be effective in therapy of Crohn disease (CD) in a phase 2b clinical trial. However, the precise role of IL12p40 in the pathogenesis of inflammatory bowel disease (IBD) was still poorly understood. In this study, we investigated the expressions of IL12p40 and its receptor interleukin-12 receptor β 1 both locally and systemically in IBD cases and healthy controls, and the contribution of IL12p40 in IBD pathogenesis. We found that the expression of IL12p40 was elevated both at messenger RNA and protein levels systematically and locally in IBD patients but more significantly in CD patients. Our genetic association study revealed that the polymorphisms of IL12B rs6887695 were associated with both CD and ulcerative colitis (UC) susceptibility in Chinese population, but did not affect the serum IL12p40 level in either CD patients or UC patients. In addition, CD4⁺ T cells isolated from peripheral blood of CD patients secreted the most abundant IL12p40 production, compared with the UC patients and healthy controls. We also found for the first time that neutralizing IL12p40 secretion could inhibit proliferation, enhance apoptosis, induce a G0/G1 arrest, restrain T helper 1 type immune responses, and promote chemokine C-C motif ligand 20-mediated migration of human CD4⁺ T cells, which might be the mechanisms why anti-IL12p40 treatment presented efficacy in CD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Asian People / genetics
  • CD4 Antigens / blood*
  • Cell Proliferation
  • Colitis, Ulcerative / blood
  • Crohn Disease / blood
  • Down-Regulation / physiology
  • Female
  • Genetic Association Studies
  • Genetic Predisposition to Disease
  • Humans
  • Inflammatory Bowel Diseases / blood*
  • Inflammatory Bowel Diseases / genetics
  • Interleukin-12 Subunit p40 / blood*
  • Interleukin-12 Subunit p40 / metabolism
  • Male
  • Middle Aged
  • RNA, Messenger / analysis
  • Up-Regulation / physiology
  • Young Adult

Substances

  • CD4 Antigens
  • Interleukin-12 Subunit p40
  • RNA, Messenger