UVB light upregulates prostaglandin synthases and prostaglandin receptors in mouse keratinocytes

Abstract

Prostaglandins belong to a class of cyclic lipid-derived mediators synthesized from arachidonic acid via COX-1, COX-2 and various prostaglandin synthases. Members of this family include prostaglandins such as PGE 2 , PGF 2α , PGD 2 and PGI 2 (prostacyclin) as well as thromboxane. In the present studies we analyzed the effects of UVB on prostaglandin production and prostaglandin synthase expression in primary cultures of undifferentiated and calcium-differentiated mouse keratinocytes. Both cell types were found to constitutively synthesize PGE 2 , PGD 2 and the PGD 2 metabolite PGJ 2 . Twenty-four hr after treatment with UVB (25 mJ/cm 2 ), production of PGE 2 and PGJ 2 increased, while PGD 2 production decreased. This was associated with increased expression of COX-2 mRNA and protein. UVB (2.5 -25 mJ/cm 2 ) also caused marked increases in mRNA expression for the prostanoid synthases PGDS, mPGES-1, mPGES-2, PGFS and PGIS, as well as expression of receptors for PGE 2 (EP1 and EP2), PGD 2 (DP and CRTH2) and prostacyclin (IP). UVB was more effective in inducing COX-2 and DP in differentiated cells and EP1 and IP in undifferentiated cells. UVB readily activated keratinocyte PI-3-kinase (PI3K)/Akt, JNK and p38 MAP signaling pathways which are known to regulate COX-2 expression. While inhibition of PI3K suppressed UVB-induced mPGES-1 and CRTH2 expression, JNK inhibition suppressed mPGES-1, PGIS, EP2 and CRTH2, and p38 kinase inhibition only suppressed EP1 and EP2. These data indicate that UVB modulates expression of prostaglandin synthases and receptors by distinct mechanisms. Moreover, both the capacity of keratinocytes to generate prostaglandins and their ability to respond to these lipid mediators are stimulated by exposure to UVB.

γ‐Tocotrienol Reduces Squalene Hydroperoxide‐Induced Inflammatory Responses in HaCaT Keratinocytes

“…COX-2 is one of the most critical enzymes related to inflammation and is required for the biosynthesis of PGE2 from arachidonic acid [36]. PGE2 induces cutaneous inflammation and modulates cellular immunity, which causes skin diseases such as atopic dermatitis [37].…”

Eicosanoids in skin inflammation

“…It exhibits potent pro-inflammatory and vasodilatory properties, promotes proliferation and modulates immunosuppression [22,23]. These effects are mediated through G-protein coupled receptors EP1-4 expressed in all primary skin cells [24][25][26][27]. PGE 2 is formed via the cytosolic and microsomal PGE synthases (cPGES, mPGES-1 and mPGES-2) [28].…”

“…Finally, prostacyclin (PGI 2 ; detected as 6-keto-PGF 1α ) and TXA 2 (detected as TXB 2 ) have been found in whole skin extracts and cultured cells in vitro, albeit at low concentrations and it is possible that they may also be products of vascular endothelial cell or derive from infiltrating leukocytes [21,31]. IP and TP receptors have been identified in keratinocytes and other skin cells [24,52] and their prevalence has been linked to PGI 2 and TXA 2 signalling events accompanied cutaneous inflammatory and immune disorders [53,54].…”

“…Up-regulation of COX-2 occurs within 3-4 hours post UVR and results in increased production of PGE 2 and PGF 2α [22], whilst the observed reduction in PGD 2 levels has been attributed to migration of epidermal Langerhan cells [125]. Studies in animals skin cells suggest UVR-induced up-regulation of prostaglandin synthase and receptor mRNA expression [24], and the catabolism of prostanoids may be temporarily reduced, as shown by studies reporting reduction in 15-PGDH mRNA and protein post UVR [126]. The expression of cutaneous 12-LOX and 15-LOX is also up-regulated following exposure to UVR with concomitant production of a range of mediators, including 8-, 9-, 11-12-and 15-HETE, and 13-HODE [22,62].…”

Cyclooxygenase-2 and tissue inhibitor of matrix metalloproteinases-1 confer the antimigratory effect of cannabinoids on human trabecular meshwork cells

“…In case of mPGES-2 this enzyme is known to be constitutively expressed in a variety of cells and coupled to COX-1 and COX-2 with modest preference for COX-2 [43]. However, mPGES-2 has also been shown to be upregulated by diverse stimuli including angiotensin II and UVB light [44,45]. A relationship between COX-2 and TIMP-1 has also been established in other cell types.…”