ATR Blockade Reduces IFN-gamma Production in Lymphocytes in Vivo and in Vitro

Kidney Int. 2005 Jun;67(6):2134-42. doi: 10.1111/j.1523-1755.2005.00318.x.

Abstract

Background: Type 1 angiotensin II (Ang II) receptor (AT(1)R) signaling induces proinflammatory responses. Recent studies suggest that T lymphocytes express AT(1)R; yet the effects of Ang II binding to AT(1)R on T cells are poorly understood. We examined the effect of AT(1)R blockade on release of the proinflammatory cytokine, interferon-gamma (IFN-gamma) by human lymphocytes in vivo and in vitro.

Methods: We used an AT(1)R blocker losartan in a randomized clinical trial in kidney transplant recipients over a 12-month period [AT(1)R blocker (N= 11) and control (N= 10)]. Peripheral blood lymphocytes, isolated from both cohorts, were analyzed by enzyme-linked immunosorbent spot assays (ELISPOT) analyses and real-time reverse transcription-polymerase chain reaction (RT-PCR) to enumerate IFN-gamma producing T cells and IFN-gamma mRNA levels. The effects of AT(1)R blockade in vitro were assessed using human alloreactive T cells and an IFN-gamma producing human cytotoxic T-lymphocyte line. Alloreactive T cells were treated with losartan or candesartan and enzyme-linked immunosorbant assay (ELISA) was used to measure IFN-gamma protein release. The cytotoxic T-lymphocyte line also was AT(1)R blocker-treated prior to determining IFN-gamma producing cells by intracellular cytokine staining.

Results: The AT(1)R blocker cohort had a significant decrease in IFN-gamma producing peripheral blood lymphocytes (P< or = 0.05 for each time point) and IFN-gamma mRNA levels (P= 0.01 vs. control patients). Losartan also decreased IFN-gamma production (P < 0.001) in purified alloreactive T cells in vitro as did candesartan. Moreover, Ang II amplified IFN-gamma generation (P < 0.05) in alloreactive T cells while AT(1)R blocker treatment inhibited Ang II's effect (P < 0.04). AT(1)R blocker treatment furthermore also inhibited IFN-gamma production in the cytotoxic T-lymphocyte line.

Conclusion: AT(1)R blockers may have a clinically relevant immunomodulatory role by blocking IFN-gamma production in T cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Aged
  • Angiotensin II / pharmacology
  • Angiotensin II Type 1 Receptor Blockers / pharmacology*
  • Benzimidazoles / pharmacology
  • Female
  • Humans
  • Interferon-gamma / biosynthesis*
  • Interferon-gamma / genetics
  • Losartan / pharmacology
  • Lymphocyte Activation
  • Lymphocytes / metabolism*
  • Male
  • Middle Aged
  • Polymerase Chain Reaction
  • RNA, Messenger / analysis
  • Tetrazoles / pharmacology

Substances

  • Angiotensin II Type 1 Receptor Blockers
  • Benzimidazoles
  • RNA, Messenger
  • Tetrazoles
  • Angiotensin II
  • Interferon-gamma
  • Losartan
  • candesartan