Molecular and Cellular Biochemistry

, Volume 428, Issue 1–2, pp 119–128 | Cite as

Interleukin-18-induced cell adhesion molecule expression is associated with feedback regulation by PPAR-γ and NF-κB in Apo E−/− mice

  • Owais Mohammad Bhat
  • P. Uday Kumar
  • N. Harishankar
  • L. Ravichandaran
  • A. Bhatia
  • Veena Dhawan
Article

Abstract

Focal recruitment of monocytes and lymphocytes is one of the earliest detectable cellular responses in atherosclerotic lesion formation. Endothelium may regulate leukocyte recruitment by expressing specific adhesion molecules. Interleukin-18 is a proinflammatory cytokine that plays an important role in vascular pathologies. The present study highlights the modulation of adhesion molecules and PPAR-γ by IL-18 and proposes a novel feedback mechanism by which PPAR-γ may regulate IL-18 expression. Three groups of normal chow diet-fed, male Apo E−/− mice, aged 12 weeks (n = 6/group) were employed: Gp I, phosphate-buffered saline (PBS) (2 mo): Gp II, recombinant IL-18 (rIL-18) (1 mo) followed by PBS (1 mo); Gp III, rIL-18 (1 mo) followed by pyrrolidine dithiocarbamate (PDTC) (1 mo). Significantly augmented mRNA expression of ICAM-1 (~5.7-fold), VCAM-1 (~3.6-fold), and NF-κB (~7-fold) was observed in Gp II mice as compared to Gp I, whereas PPAR-γ expression was not altered. PDTC treatment caused a significant downregulation of ICAM-1 (~4.2-fold), VCAM-1(~2-fold), and NF-κB (~4.5-fold) and upregulation of PPAR-γ expression (~5-fold) in Gp III mice. A similar trend was observed in protein expression. In vivo imaging results demonstrated a marked increase in probe (CF750 dye conjugated to VCAM-1 antibody) fluorescence intensity for VCAM-1 expression in Gp II mice, whereas it was moderately decreased in Gp III. PPAR-γ was found to significantly downregulate both IL-18 levels and IL-18-induced adhesion molecules. The underlying mechanism was found to be via inhibition of NF-κB activity by PDTC, thereby leading to decreased adherence of monocytes to the activated endothelial cells and a step to halt the progression and development of atherosclerotic lesions.

Keywords

Recombinant IL-18 ICAM-1 VCAM-1 PPAR-γ PDTC 

Notes

Acknowledgements

We thank Dr. B. Sesikeran, Director, National Institute of Nutrition (NIN), Hyderabad for providing facilities at NIN for carrying out the research work.

Funding

We thank the Department of Biotechnology, New Delhi, India, for providing the financial support.

Compliance with ethical standards

Disclosure

None.

Ethical approval

The animal protocol was approved by the Institute Animal Ethics Committee (IAEC) of PGIMER, Chandigarh (Ref. No. 49/IAEC/227). All the animal procedures were performed following National Institute of Health protocol.

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Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Owais Mohammad Bhat
    • 1
    • 3
  • P. Uday Kumar
    • 2
  • N. Harishankar
    • 2
  • L. Ravichandaran
    • 2
  • A. Bhatia
    • 1
  • Veena Dhawan
    • 1
  1. 1.Department of Experimental Medicine and BiotechnologyResearch Block-B, Postgraduate Institute of Medical Education and Research (PGIMER)ChandigarhIndia
  2. 2.Department of Histopathology, National Centre for Laboratory Animal Sciences (NCLAS)National Institute of Nutrition (NIN)HyderabadIndia
  3. 3.Department of Pharmacology and Toxicology Virginia Common Wealth UniversityRichmondUSA

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