Interleukin-18-induced cell adhesion molecule expression is associated with feedback regulation by PPAR-γ and NF-κB in Apo E-/- mice.
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.
Department of Experimental Medicine and Biotechnology, Research Block-B, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, 160012, India.|Department of Pharmacology and Toxicology, Virginia Common Wealth University, Richmond, VA, USA.
Owais Mohammad
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Bhat
Department of Histopathology, National Centre for Laboratory Animal Sciences (NCLAS), National Institute of Nutrition (NIN), Hyderabad, India.
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Uday Kumar
Department of Histopathology, National Centre for Laboratory Animal Sciences (NCLAS), National Institute of Nutrition (NIN), Hyderabad, India.
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Harishankar
Department of Histopathology, National Centre for Laboratory Animal Sciences (NCLAS), National Institute of Nutrition (NIN), Hyderabad, India.
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Ravichandaran
Department of Experimental Medicine and Biotechnology, Research Block-B, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, 160012, India.
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Bhatia
Department of Experimental Medicine and Biotechnology, Research Block-B, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, 160012, India. veenad2001@yahoo.com.
Veena
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Dhawan
D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics*; D050197:Atherosclerosis / Q000235:genetics*; D002448:Cell Adhesion / Q000187:drug effects; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000494:pharmacology; D004195:Disease Models, Animal; D025461:Feedback, Physiological / Q000187:drug effects*; D005786:Gene Expression Regulation; D006801:Humans; D020382:Interleukin-18 / Q000008:administration & dosage* / Q000494:pharmacology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics* / Q000378:metabolism; D047495:PPAR gamma / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction
D001057:Apolipoproteins E; D015815:Cell Adhesion Molecules; D020382:Interleukin-18; D016328:NF-kappa B; D047495:PPAR gamma
ICAM-1; PDTC; PPAR-γ; Recombinant IL-18; VCAM-1