PPARδ inhibits UVB-induced secretion of MMP-1 through MKP-7-mediated suppression of JNK signaling.

In the present study, we investigated the role of peroxisome proliferator-activated receptor (PPAR) δ in modulating matrix-degrading metalloproteinases and other mechanisms underlying photoaging processes in the skin. In human dermal fibroblasts (HDFs), activation of PPARδ by its specific ligand GW501516 markedly attenuated UVB-induced secretion of matrix metalloproteinase (MMP)-1, concomitant with decreased generation of reactive oxygen species. These effects were significantly reduced in the presence of PPARδ small interfering RNA and GSK0660. Furthermore, c-Jun N-terminal kinase (JNK), but not p38 or extracellular signal-regulated kinase, mediated PPARδ-dependent inhibition of MMP-1 secretion in HDFs exposed to UVB. PPARδ-mediated messenger RNA stabilization of mitogen-activated protein kinase phosphatase (MKP)-7 was responsible for the GW501516-mediated inhibition of JNK signaling. Inhibition of UVB-induced secretion of MMP-1 by PPARδ was associated with the restoration of types I and III collagen to levels approaching those in cells not exposed to UVB. Finally, in HR-1 hairless mice exposed to UVB, administration of GW501516 significantly reduced wrinkle formation and skin thickness, downregulated MMP-1 and JNK phosphorylation, and restored the levels of MKP-7, types I and III collagen. These results suggest that PPARδ-mediated inhibition of MMP-1 secretion prevents some effects of photoaging and maintains the integrity of skin by inhibiting the degradation of the collagenous extracellular matrix.

Suppression of tumor necrosis factor-alpha and inducible nitric oxide synthase gene expression by THI 52, a new synthetic naphthyl-benzylisoquinoline alkaloid.

The effects of THI 52 (1-naphthylethyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline) on (a) inducible nitric oxide synthase (iNOS) and tumor necrosis factor-alpha (TNF-alpha) expression in RAW 264.7 cells stimulated by lipopolysaccharide (LPS)/interferon gamma (IFN-gamma), (b) plasma nitrate concentration as well as iNOS protein expression (lung) in vivo in LPS-treated rats, and (c) the restoration of vascular contractility to vasoconstrictor agents in LPS-treated vessels in vitro were investigated. THI 52 concentration-dependently reduced not only nitric oxide (NO) production (IC(50) value, 12.5 microM) but also the expression of TNF-alpha and iNOS mRNA in RAW 264.7 cells. Incubation of rat endothelium-denuded thoracic aorta with LPS (300 ng/mL) in vitro for 8 hr resulted in the suppression of vasoconstrictor effects to phenylephrine (PE), effects that were restored by co-incubation with THI 52. Administration of THI 52 (10 and 20mg/kg, i.p.) 30 min before injection of LPS (10mg/kg, i.p.) resulted in a significant reduction of the expression of iNOS protein in rat lung tissue and in the plasma nitrite/nitrate (NOx) level. Addition of THI 52-treated macrophage-conditioned medium to a TNF-sensitive L929 fibroblast cell line (CCL1) increased cell viability, depending on the concentration of THI 52. Finally, THI 52 inhibited the activation of nuclear factor kappaB (NF-kappaB) by inhibition of IkappaB degradation through the prevention of IkappaB phosphorylation. Collectively, these results strongly suggest that THI 52 suppresses both TNF-alpha and iNOS gene expression by inhibiting NF-kappaB. Thus, THI 52, a new synthetic isoquinoline alkaloid, may be beneficial in inflammatory disorders where the overproduction of NO and TNF-alpha is a matter of concern.