Prostaglandin E₂inhibits fibroblast chemotaxis

Abstract

Fibroblasts are the major source of extracellular connective tissue matrix, and the recruitment, accumulation, and stimulation of these cells are thought to play important roles in both normal healing and the development of fibrosis. Prostaglandin E(2) (PGE(2)) can inhibit this process by blocking fibroblast proliferation and collagen production. The aim of this study was to investigate the inhibitory effect of PGE(2) on human plasma fibronectin (hFN)- and bovine bronchial epithelial cell-conditioned medium (BBEC-CM)-induced chemotaxis of human fetal lung fibroblasts (HFL1). Using the Boyden blind well chamber technique, PGE(2) (10(-7) M) inhibited chemotaxis to hFN 40.8 +/- 5.3% (P < 0.05) and to BBEC-CM 49.7 +/- 11.7% (P < 0.05). Checkerboard analysis demonstrated inhibition of both chemotaxis and chemokinesis. The effect of PGE(2) was concentration dependent, and the inhibitory effect diminished with time. Other agents that increased fibroblast cAMP levels, including isoproterenol (10(-5) M), dibutyryl cAMP (10(-5) M), and forskolin (3 x 10(-5) M) had similar effects and inhibited chemotaxis 54.1, 95.3, and 87.0%, respectively. The inhibitory effect of PGE(2) on HFL1 cell chemotaxis was inhibited by the cAMP-dependent protein kinase (PKA) inhibitor KT-5720, which suggests a cAMP-dependent effect mediated by PKA. In summary, PGE(2) appears to inhibit fibroblast chemotaxis, perhaps by modulating the rate of fibroblast migration. Such an effect may contribute to regulation of the wound healing response after injury.

Prostaglandin E2 possesses different potencies in inducing Vascular Endothelial Growth Factor and Interleukin-8 production in COPD human lung fibroblasts

“…In order to assess if this differential effect could be observed also using biologically synthesized PGE 2 …”

“…PGE 2 has the potential to function as both an autocrine and a paracrine mediator in fibroblasts, affecting chemotactic recruitment [2][3], proliferation [4], matrix production [5,6], and matrix remodeling [7,8]. PGE 2 acts on four distinct G proteincoupled E-prostanoid (EP) receptors named EP1, EP2, EP3, and EP4, [9,10], and coupled to different transduction mechanisms such as the increase in intracellular cyclic adenosine monophosphate (cAMP, EP2 and EP4), the decrease in cAMP (EP3), and the increase in intracellular calcium (EP1) [11] [12].…”

Prostaglandin D2inhibits fibroblast migration

“…In the current study, in contrast, the ability of PGD 2 to inhibit fibroblast chemotaxis appears to be mediated through the DP receptor and not through the TP receptor. In this context, the effect of PGD 2 is similar to other agents that also inhibit fibroblast chemotaxis by increasing intracellular cAMP levels [24].…”

“…Mast cells are believed to be a prominent source of PGD 2 [5,22], and increased levels of PGD 2 have been reported in lavage fluid from asthmatics [23]. Other prostaglandins, for example prostaglandin E 2 (PGE 2 ), also have been shown to modulate mesenchymal cell chemotaxis [24]. Interestingly, PGE 2 can inhibit fibroblast chemotaxis but accelerates epithelial cell wound closure, suggesting that prostanoids may exert a variety of effects on cells participating in wound repair [25].…”

Cellular and Molecular Mechanisms of Chronic Inflammation-Associated Organ Fibrosis

“…Leukotrienes (LTs) not only induce fibroblast migration, proliferation, and matrix protein synthesis, but also promote fibrosis through the stimulation and activation of TGFβ (Shim et al, 2006). On the contrary, prostaglandin E 2 (PGE 2 ), which has well established anti-inflammatory activities, may suppress fibrosis by inhibiting the proliferation, migration, and differentiation of myofibroblasts (Kohyama et al, 2001;Lama et al, 2002;Thomas et al, 2007). Recent studies have demonstrated that PGF2a receptor deficient mice are resistant against bleomycininduced lung fibrosis (Oga et al, 2009), and that LTB4 receptor inhibitors and LPA1 inhibitors suppress bleomycin-induced lung fibrosis (Tager et al, 2008).…”