E. Boisvieux-ulrich et al., Differential effects of several retinoid receptor-selective ligands on squamous differentiation and apoptosis in airway epithelial cells, CELL TIS RE, 300(1), 2000, pp. 67-81
The roles of the different retinoid receptors on the differentiation of rab
bit tracheal epithelial (RbTE) cells in primary culture were analysed using
selective agonists for the retinoid acid receptor subtypes RAR alpha (CD33
6), RAR beta (CD2019), RAR gamma (CD437), an RAR panagonist (CD367), a reti
noid X receptor RXR panagonist (CD2624) and an antagonist for RAR beta/gamm
a (CD2665). Squamous differentiation was assessed via expression of cytoker
atins CK13/CK4 and transglutaminase I (TGI), specific markers of metaplasia
. Treatment with RARa and beta agonists or RAR panagonist, but not the RAR
gamma agonist or RXR agonist, is required for the inhibition of squamous me
taplasia, evidenced by inhibition of CK13/CK4 and TGI expression. The expre
ssion of CK10 cytokeratin of keratinizing epithelia, CK14/CK5 basal cell cy
tokeratins, and CK6 marker of cell proliferation decreases upon exposure of
the RAR alpha/beta and RXR agonists. The RAR gamma agonist CD437, inactive
in the decrease in CK13/CK4, CK10 and CK14, reduces CK5/CK6 amounts. CD437
is responsible for a dose-dependent apoptotic response. Nuclear labelling
with propidium iodide (PI) and electron microscopy revealed chromatin conde
nsation and nuclear fragmentation. DNA cleavage and cell fragmentation were
confirmed by enzyme-linked immunosorbent assay (ELISA) and flow cytometry,
The RAR beta gamma antagonist was also slightly active. The results indica
te that CD437 causes growth arrest in the early S-phase of the cell cycle a
nd prevents the transition G(1)-S-phase. CD437 was demonstrated to induce a
poptosis in the S-phase cells identified by bromodeoxyuridine (BrdU) incorp
oration. In conclusion, RAR alpha/beta ligands are effective inhibitors of
squamous differentiation. On the contrary, RAR gamma ligand appears to be i
nefficient in metaplasia inhibition, but the selective RAR gamma agonist CD
437 induces growth arrest and apoptosis of basal proliferative cells.