Human β-defensin-3 up-regulates cyclooxygenase-2 expression and prostaglandin E₂synthesis in human gingival fibroblasts

Abstract

These findings indicate that epithelial human beta-defensin-3 functions as a proinflammatory mediator in controlling arachidonic acid metabolism in underlying fibroblasts.

Involvement of the P2X₇ Purinergic Receptor and c-Jun N-Terminal and Extracellular Signal-Regulated Kinases in Cyclooxygenase-2 and Prostaglandin E₂ Induction by LL-37

“…Our findings identify an additional function and a role of LL-37 in the modulation of mucosal immunity in the oral cavity, since both COX-2 and PGE 2 play an important role in the pathogenesis of periodontal disease [14]. Similarly to IL-1β-induced PGE 2 formation, which is mediated by enhanced COX-2 gene expression in gingival fibroblasts [15], PGE 2 levels were also raised by LL-37 via the specificity of COX-2 activation, consistent with our previous result showing that elevated PGE 2 levels by hBD-3 treatment result from induced COX-2 expression [17]. The inducible effect of LL-37 on COX-2 expression and PGE 2 production in HGFs is relevant to the increased activity of phospholipase A 2 , an upstream molecule involved in arachidonic acid metabolism, induced by LL-37 in mouse submandibular acinar cells [26].…”

“…2c). Taken together, similar to the inducible effects of hBD-3 on COX-2 expression, resulting in elevated PGE 2 production in HGFs [17], LL-37 can also upregulate both COX-2 expression and PGE 2 synthesis in HGFs. Furthermore, both hBD-3- and LL-37-challenged HGFs produce PGE 2 via de novo synthesis of COX-2.…”

“…However, from the time-course experiment, some differences were noted between the inducible effects of hBD-3 and those of LL-37. Whereas hBD-3 cumulatively induces COX-2 expression and PGE 2 synthesis [17], LL-37 does so transiently, suggesting different signaling pathways used to mediate COX-2 expression between hBD-3 and LL-37.…”

“…The RT-PCR protocol has been described previously [17]. Briefly, 3 µg of total RNA were used for synthesis of complementary DNA (cDNA) by SuperScript™ first-strand cDNA system reagents (Fermentas, Hanover, Md., USA) and a primer pair specific for COX-1, COX-2, or GAPDH, as described in table 1.…”

“…Moreover, we previously reported that, among three human β-defensins (hBDs) that are expressed in the oral cavity [16], only hBD-3 can induce COX-2 mRNA and protein expression, resulting in elevated PGE 2 production in HGFs [17]. Although LL-37 was reported to upregulate the expression of COX-2 and inhibitor of apoptosis-2, implicated in the COX-2/PGE 2 anti-apoptotic pathway in skin keratinocytes [18], it is still unknown whether LL-37 can activate COX-2 expression in HGFs.…”