Changes in Arachidonic Acid Metabolism in UV-Irradiated Hairless Mouse Skin

Ruzicka, Thomas; Walter, Joseph F.; Printz, Morton P.

doi:10.1111/1523-1747.ep12519287

Cited by 66 publications

(27 citation statements)

References 15 publications

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“…UVB was also found to cause marked increases in PGJ 2 in keratinocytes, but to reduce PGD 2 production. Decreased production of PGD 2 is consistent with an earlier report demonstrating that UVB suppressed production of this arachidonic acid metabolite in hairless mouse skin (Ruzicka et al, 1983). PGD 2 is relatively unstable and degrades by spontaneous dehydration and isomerization reactions to PGJ 2 which is metabolized to a variety of biological active metabolites (Kikawa et al, 1984).…”

Section: Discussionsupporting

confidence: 91%

“…Each of these prostaglandins or their metabolites is known to be important in regulating cell growth, and their constitutive production in keratinocytes is presumably important in skin homeostasis (Fogh and Kragballe, 2000). As previously observed in mouse and human skin (Black et al, 1980b;Ruzicka et al, 1983), UVB stimulated production of PGE 2 in undifferentiated and differentiated cultures of primary mouse keratinocytes. PGE 2 is a potent proinflammatory mediator and it has been shown to play a key role in the development of UVB-induced skin cancer (Furstenberger et al, 1989).…”

Section: Discussionmentioning

confidence: 73%

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UVB light upregulates prostaglandin synthases and prostaglandin receptors in mouse keratinocytes

Black

Gray

Shakarjian

et al. 2008

Toxicology and Applied Pharmacology

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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.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 73%

UVB light upregulates prostaglandin synthases and prostaglandin receptors in mouse keratinocytes

Black

Gray

Shakarjian

et al. 2008

Toxicology and Applied Pharmacology

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“…Moreover, several studies showed that PGE 2 production is induced by numerous stimuli, including known skin tumor promoters such as UV irradiation (10,11) and 12-O-tetradecanoylphorbol-13-acetate (TPA; refs. 12, 13).…”

Section: Introductionmentioning

confidence: 99%

Multiple Signaling Pathways Are Responsible for Prostaglandin E2–Induced Murine Keratinocyte Proliferation

Ansari

Rundhaug

Fischer

2008

Molecular Cancer Research

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Although prostaglandin E 2 (PGE 2 ) has been shown by pharmacologic and genetic studies to be important in skin cancer, the molecular mechanism(s) by which it contributes to tumor growth is not well understood. In this study, we investigated the mechanisms by which PGE 2 stimulates murine keratinocyte proliferation using in vitro and in vivo models. In primary mouse keratinocyte cultures, PGE 2 activated the epidermal growth factor receptor (EGFR) and its downstream signaling pathways as well as increased cyclic AMP (cAMP) production and activated the cAMP response element binding protein (CREB). EGFR activation was not significantly inhibited by pretreatment with a c-src inhibitor (PP2), nor by a protein kinase A inhibitor (H-89). However, PGE 2 -stimulated extracellularly regulated kinase 1/2 (ERK1/2) activation was completely blocked by EGFR, ERK1/2, and phosphatidylinositol 3-kinase (PI3K) pathway inhibitors. In addition, these inhibitors attenuated the PGE 2 -induced proliferation, nuclear factor-KB, activator protein-1 (AP-1), and CREB binding to the promoter regions of the cyclin D1 and vascular endothelial growth factor (VEGF) genes and expression of cyclin D1 and VEGF in primary mouse keratinocytes. Similarly, in vivo, we found that WT mice treated with PGE 2 and untreated cyclooxygenase-2 -overexpressing transgenic mice had higher levels of cell proliferation and expression of cyclin D1 and VEGF, as well as higher levels of activated EGFR, nuclear factor-KB, AP-1, and CREB, than vehicle-treated WT mice. Our findings provide evidence for a link between cyclooxygenase-2 overexpression and EGFR-, ERK-, PI3K-, cAMP-mediated cell proliferation, and the tumor-promoting activity of PGE 2 in mouse skin.

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“…As blocking of prostanoid production by treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) treatment can abolish the immunosuppressive effect through UV (Chung et al, 1986;Hart et al, 2002;Walterscheid et al, 2002), it has been suspected that prostanoids play important roles in the UV-induced immunosuppression, especially in Treg induction. By UV radiation, various prostanoids are produced in the skin, with PGE 2 being the most abundant prostanoids (Kuwamoto et al, 2000;Ruzicka et al, 1983;Soontrapa et al, 2011). Recently, it has been revealed that PGE 2 -EP4 signaling mediates the induction of Treg by UV irradiation, and regulates UV-induced immunosuppression (Soontrapa et al).…”

Section: Prostanoids and Treg Inductionmentioning

confidence: 99%