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COX-2 as a novel target of CRF family peptides’ participating in inflammation
Biochemical and Biophysical Research Communications 382 (2009) 483–485
Contents lists available at ScienceDirect
Biochemical and Biophysical Research Communications journal homepage: www.elsevier.com/locate/ybbrc
Mini Review
COX-2 as a novel target of CRF family peptides’ participating in inflammation Rongjian Zhang, Shengnan Li * Department of Pharmacology, Nanjing Medical University, 140 Hanzhong Road, Nanjing 210029, PR China
a r t i c l e
i n f o
Article history: Received 28 February 2009 Available online 16 March 2009
Keywords: Urocortin Corticotropin-releasing factor Corticotropin-releasing factor receptor Cyclooxygenase-2 Inflammation
a b s t r a c t In mammals, corticotropin-releasing factor (CRF) family peptides include CRF, Urocortin (Ucn) 1, Ucn2, and Ucn3. In contrast to their systemic indirect immunosuppressive effects on the hypothalamic–pituitary adrenal axis, CRF family peptides act as locally expressed autocrine or paracrine pro-inflammatory factors in a series of inflammatory diseases. Cyclooxygenase-2 (COX-2), the rate-limiting enzyme in metabolism of arachidonic acid, has been abundantly reported to take part in inflammatory diseases. Recently, reports indicate that CRF family peptides may play an important role in the regulation of COX-2 under inflammatory conditions. Moreover, CRF receptors are involved in this process. This review aims to highlight the current novel findings on regulation of COX-2 by CRF family peptides in inflammation. Furthermore, the relevant mechanisms are discussed. Ó 2009 Published by Elsevier Inc.
Since corticotropin-releasing factor (CRF) was first characterized in 1981 [1], a growing family of ligands and receptors has been discovered [2]. In mammals, the family members include CRF, Urocortin (Ucn) 1, Ucn2, and Ucn3, along with two receptors, CRFR1 and CRFR2, and a CRF binding protein [2]. Recently, CRF family peptides have been considered to be potent immunomodulatory factors which participate in immune responses [3]. Furthermore, many reports indicate that CRF family peptides participate in a series of inflammatory diseases as pro-inflammatory mediators [3–10]. On the other hand, Cyclooxygenase-2 (COX-2), the ratelimiting enzyme in metabolism of arachidonic acid, has been abundantly reported to take part in inflammatory diseases [11–12]. The pro-inflammatory mediators, such as interleukin-1 (IL-1), tumor necrosis factor alpha (TNF-a) and lipopolysaccharide (LPS), have been shown to induce COX-2 expression [11]. However, CRF family peptides’ pro-inflammatory function on modulating COX-2 has rarely been illustrated. This overview aims to highlight the recent findings on regulation of COX-2 by CRF family peptides in inflammation. Furthermore, the relevant mechanisms are discussed. CRF family peptides and inflammation In contrast to their systemic indirect immunosuppressive effects on the hypothalamic–pituitary adrenal axis, CRF family peptides act as locally expressed autocrine or paracrine proinflammatory factors in a series of inflammatory diseases, such as rheumatoid arthritis and osteoarthritis [4] and ulcerative colitis [5]. Moreover, CRF family peptides can stimulate the release of pro* Corresponding author. Fax: +86 25 86863050. E-mail addresses: [email protected], [email protected] (S. Li). 0006-291X/$ - see front matter Ó 2009 Published by Elsevier Inc. doi:10.1016/j.bbrc.2009.03.064
inflammatory mediators under inflammatory conditions [5,6]. Our previous study demonstrated the over-expression of Ucn1 in lung tissues of rats with allergic asthma [7]; and inhalation aerosol of Ucn1 could increase pulmonary vascular permeability via mast cell infiltration and activation [8]. We demonstrated for the first time that mast cell degranulation induced by Ucn1 was realized through increasing intracellular calcium concentration via CRFR1 [9]. Moreover, our data showed CRF played a significant role in promoting the development of atherosclerosis [10]. All these evidences suggest that CRF family peptides may participate in the pathophysiology of many inflammatory conditions as pro-inflammatory mediators. CRF family peptides and COX-2 in inflammation There are many reports indicating that CRF family peptides could induce COX-2 expression under a series of inflammatory conditions [13–15]. CRF signaling is an important component of the inflammatory cascade in human arthritis [13,16]; while COX2 level indicates the degree of inflammation in rheumatic arthritis (RA) synovial tissue [17]. It was found that CRF contributed significantly to PGE2 (a major COX-2 product) levels in a timeand dose-dependent manner in RA synovial tissue [13]. Furthermore, selective COX-2 inhibition completely prevented the production of CRF-induced PGE2 [13,14]. Thromboangiitis obliterans (TAO) is defined as a vasculitis [18]. Our recent study showed that in sodium laurate induced TAO model rats, plasma Ucn1 and PGE2 levels were elevated and the expressions of Ucn1 and COX-2 from rat femoral arteries were markedly increased; furthermore, Ucn1 application aggravated vasculitis and augmented COX-2 and PGE2 expression (original article accepted by Br. J. Phar-
484
R. Zhang, S. Li / Biochemical and Biophysical Research Communications 382 (2009) 483–485
macol.). In addition, our present data demonstrated that Ucn1 exerted a pro-inflammatory function by augmenting COX-2 and PGE2 expression in LPS-induced rat aortic endothelial cells (unpublished data). Recently, COX-2 pathway is involved in regulation of Ucnmediated pro-inflammatory cytokine productions [14,15]. Macrophages are targets of CRF family peptides [19–21]. In LPS-activated macrophages, CRF, Ucn1 and Ucn2 transiently suppressed the release of TNF-a while enhanced COX-2 expression and PGE2 release [14]. COX-2 inhibitor application demonstrated COX-2 and PGE2 were responsible for CRF family peptides-induced suppression of TNF-a release [14]. Furthermore, COX-2 pathway was found to be involved in regulation of Ucn-increased IL-6 production in rat aortic smooth muscle cells [15]. Taken together, CRF family peptides may participate in the pathophysiology of many inflammatory conditions via COX-2 pathway.
NF-jB activation [37]; while Ucn2 has pro-inflammatory effects in human intestinal cells by phosphorylation of NF-jB and degradation of IjBa [38]. Therefore, converging lines of evidence strongly support the relationship between CRF family peptides and COX-2 in signal transduction pathways. Recently, reports demonstrate that CRF family peptides and COX-2 share similar signal transduction pathways under inflammatory conditions [13,14]. In LPS-activated macrophages, the effect of CRF family peptides on COX-2 expression was mediated via PI3K and p38MAPK [14]. In RA synovial tissue, COX-2-dependent PGE2 production by CRF was confirmed to be due to the transcriptional activation of CREB/ATF [13]. Moreover, the stimulatory effects of both CRF and PGE2 on gene transcription have been shown to be mediated through cAMP/PKA/CREB dependent activation [13,39,40]. Thus, all these evidences may partially reveal the intrinsic relationship between CRF family peptides and COX-2 in inflammation.
CRF receptors and COX-2 Conclusion CRF has been reported to induce COX-2 expression in many tissues, such as RA synovial tissue [13] and human fetal membrane [22]. As CRF has 10-fold higher affinity for CRFR1 than for CRFR2 [2,3], the above COX-2 expression might be mediated by CRFR1. This was further confirmed by our recent study (original article accepted by Br. J. Pharmacol.). In sodium laurate induced TAO model rats, Ucn1-mediated COX-2 and PGE2 expression could be abolished by CRFR1 antagonist, NBI-27914 while CRFR2 antagonist, antisauvagine-30, could not. On the other hand, CRFR2 are also involved in COX-2 expression [14,15]. Kageyama et al. reported that in rat aortic smooth muscle cells, Ucn1 and Ucn2 induced the expression of COX-2 in a time- and dose-dependent manner via CRFR2 [15]. However, in LPS-activated macrophages, CRF, Ucn1 and Ucn2 transiently increased COX-2 and PGE2 synthesis [14]. For CRF having much higher affinity for CRFR1 while Ucn2 being selective for CRFR2 [2,3], the above effects were mediated by both CRFR1 and CRFR2. Furthermore, both CRFR1 antagonist a-helicalCRF and CRFR2 antagonist anti-sauvagine-30 blocked the effect of the neuropeptides on PGE2 release [14]. Taken together, all these evidences suggest that both CRFR1 and CRFR2 activations could increase COX-2 expression. However, recently, Gao et al. reported that CRF family peptides acted on CRFR1 and CRFR2 to exert different effects on COX-2 production in cultured human placental trophoblasts [23]. Placental trophoblasts expressed both CRFR1 and CRFR2 [23,24]. Treatment of cultured human placental trophoblast cells with exogenous CRF and Ucn1 showed an increase of COX-2 expression while Ucn2 or Ucn3 decreased COX-2 expression. Moreover, CRFR1 antagonist Antalarmin reduced COX-2 expression whereas CRFR2 antagonist astressin2b increased COX-2 expression [23]. Signaling networks between CRF family peptides and COX-2 Lots of evidences suggest the potential signaling networks between CRF family peptides and COX-2 [25–38]. On the one hand, the effects of CRF family peptides are mediated by two high-affinity receptors CRFR1 and CRFR2, both of which are Gsa/adenylyl cyclase/cAMP-coupled G-protein coupled receptors [25]. In addition, mitogen-activated protein kinases (MAPKs), Akt and nuclear factor kappa B (NF-jB) have been implicated as key signaling intermediates downstream of CRF receptors activation [26–31]. On the other hand, the expression of COX-2 is regulated by MAPKs [32–34], Akt [35] and several transcription factors including the cAMP response element binding (CREB), activating transcription factor (ATF) and NF-jB [35,36]. Furthermore, COX-2 is now considered to be NFjB regulated inflammatory genes which can be induced after
As potent pro-inflammatory mediators, CRF family peptides could induce COX-2 expression and PGs release in many inflammatory conditions. CRF receptors are involved in the process. Furthermore, CRF family peptides and COX-2 share similar signal transduction pathways under inflammatory conditions. In summary, COX-2 may be an important target of CRF family peptides’ participating in a sort of inflammatory diseases. Acknowledgments This work was supported by Key Project from Natural Scientific Foundation of Jiangsu Province (No. BK2006727), Project from New Century Excellent Talents (No. NCET-06-0507) and Project funded by the Summit of the ‘‘Six Great Talents” of Jiangsu Province (06C-017). References [1] W. Vale, J. Spiess, C. Rivier, J. Rivier, Characterization of a 41-residue ovine hypothalamic–peptide that stimulates secretion of corticotropin and betaendorphin, Science 213 (1981) 1394–1397. [2] T.L. Bale, W. Vale, CRF and CRF receptors: role in stress responsivity and other behaviors, Annu. Rev. Pharmacol. Toxicol. 44 (2004) 525–557. [3] E.M. Fekete, E.P. Zorrilla, Physiology, pharmacology, and therapeutic relevance of urocortins in mammals: ancient CRF paralogs, Front. Neuroendocrinol. 28 (2007) 1–27. [4] M. Kohno, Y. Kawahito, Y. Tsubouchi, A. Hashiramoto, R. Yamada, K.I. Inoue, Y. Kusaka, T. Kubo, I.J. Elenkov, G.P. Chrousos, M. Kondo, H. Sano, Urocortin expression in synovium of patients with rheumatoid arthritis and osteoarthritis: relation to inflammatory activity, J. Clin. Endocrinol. Metab. 86 (2001) 4344–4352. [5] M. Saruta, K. Takahashi, T. Suzuki, A. Torii, M. Kawakami, H. Sasano, Urocortin 1 in colonic mucosa in patients with ulcerative colitis, J. Clin. Endocrinol. Metab. 89 (2004) 5352–5361. [6] T.C. Theoharides, J.M. Donelan, N. Papadopoulou, J. Cao, D. Kempuraj, P. Conti, Mast cells as targets of corticotropin-releasing factor and related peptides, Trends Pharmacol. Sci. 25 (2004) 563–568. [7] Y. Wu, H. Zhou, Y. Xu, S. Li, Enhanced expression of urocortin in lung tissues of rats with allergic asthma, Biochem. Biophys. Res. Commun. 341 (2006) 532– 540. [8] Y. Wu, Y. Xu, H. Zhou, J. Tao, S. Li, Expression of urocortin in rat lung and its effect on pulmonary vascular permeability, J. Endocrinol. 189 (2006) 167–178. [9] Y. Wu, J. Hu, R. Zhang, C. Zhou, Y. Xu, X. Guan, S. Li, Enhanced intracellular calcium induced by urocortin is involved in degranulation of rat lung mast cells, Cell. Physiol. Biochem. 21 (2008) 173–182. [10] Y. Wu, R. Zhang, C. Zhou, Y. Xu, X. Guan, J. Hu, Y. Xu, S. Li, Enhanced expression of vascular cell adhesion molecule-1 by corticotrophin-releasing hormone contributes to progression of atherosclerosis in LDL receptor-deficient mice, Atherosclerosis, doi:10.1016/j.atherosclerosis.2008.05.059. [11] R.N. Dubois, S.B. Abramson, L. Crofford, R.A. Gupta, L.S. Simon, L.B. Van De Putte, P.E. Lipsky, Cyclooxygenase in biology and disease, FASEB J. 12 (1998) 1063–1073. [12] G.D. Anderson, S.D. Hauser, K.L. McGarity, M.E. Bremer, P.C. Isakson, S.A. Gregory, Selective inhibition of cyclooxygenase (COX)-2 reverses
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Contents lists available at ScienceDirect
Biochemical and Biophysical Research Communications journal homepage: www.elsevier.com/locate/ybbrc
Mini Review
COX-2 as a novel target of CRF family peptides’ participating in inflammation Rongjian Zhang, Shengnan Li * Department of Pharmacology, Nanjing Medical University, 140 Hanzhong Road, Nanjing 210029, PR China
a r t i c l e
i n f o
Article history: Received 28 February 2009 Available online 16 March 2009
Keywords: Urocortin Corticotropin-releasing factor Corticotropin-releasing factor receptor Cyclooxygenase-2 Inflammation
a b s t r a c t In mammals, corticotropin-releasing factor (CRF) family peptides include CRF, Urocortin (Ucn) 1, Ucn2, and Ucn3. In contrast to their systemic indirect immunosuppressive effects on the hypothalamic–pituitary adrenal axis, CRF family peptides act as locally expressed autocrine or paracrine pro-inflammatory factors in a series of inflammatory diseases. Cyclooxygenase-2 (COX-2), the rate-limiting enzyme in metabolism of arachidonic acid, has been abundantly reported to take part in inflammatory diseases. Recently, reports indicate that CRF family peptides may play an important role in the regulation of COX-2 under inflammatory conditions. Moreover, CRF receptors are involved in this process. This review aims to highlight the current novel findings on regulation of COX-2 by CRF family peptides in inflammation. Furthermore, the relevant mechanisms are discussed. Ó 2009 Published by Elsevier Inc.
Since corticotropin-releasing factor (CRF) was first characterized in 1981 [1], a growing family of ligands and receptors has been discovered [2]. In mammals, the family members include CRF, Urocortin (Ucn) 1, Ucn2, and Ucn3, along with two receptors, CRFR1 and CRFR2, and a CRF binding protein [2]. Recently, CRF family peptides have been considered to be potent immunomodulatory factors which participate in immune responses [3]. Furthermore, many reports indicate that CRF family peptides participate in a series of inflammatory diseases as pro-inflammatory mediators [3–10]. On the other hand, Cyclooxygenase-2 (COX-2), the ratelimiting enzyme in metabolism of arachidonic acid, has been abundantly reported to take part in inflammatory diseases [11–12]. The pro-inflammatory mediators, such as interleukin-1 (IL-1), tumor necrosis factor alpha (TNF-a) and lipopolysaccharide (LPS), have been shown to induce COX-2 expression [11]. However, CRF family peptides’ pro-inflammatory function on modulating COX-2 has rarely been illustrated. This overview aims to highlight the recent findings on regulation of COX-2 by CRF family peptides in inflammation. Furthermore, the relevant mechanisms are discussed. CRF family peptides and inflammation In contrast to their systemic indirect immunosuppressive effects on the hypothalamic–pituitary adrenal axis, CRF family peptides act as locally expressed autocrine or paracrine proinflammatory factors in a series of inflammatory diseases, such as rheumatoid arthritis and osteoarthritis [4] and ulcerative colitis [5]. Moreover, CRF family peptides can stimulate the release of pro* Corresponding author. Fax: +86 25 86863050. E-mail addresses: [email protected], [email protected] (S. Li). 0006-291X/$ - see front matter Ó 2009 Published by Elsevier Inc. doi:10.1016/j.bbrc.2009.03.064
inflammatory mediators under inflammatory conditions [5,6]. Our previous study demonstrated the over-expression of Ucn1 in lung tissues of rats with allergic asthma [7]; and inhalation aerosol of Ucn1 could increase pulmonary vascular permeability via mast cell infiltration and activation [8]. We demonstrated for the first time that mast cell degranulation induced by Ucn1 was realized through increasing intracellular calcium concentration via CRFR1 [9]. Moreover, our data showed CRF played a significant role in promoting the development of atherosclerosis [10]. All these evidences suggest that CRF family peptides may participate in the pathophysiology of many inflammatory conditions as pro-inflammatory mediators. CRF family peptides and COX-2 in inflammation There are many reports indicating that CRF family peptides could induce COX-2 expression under a series of inflammatory conditions [13–15]. CRF signaling is an important component of the inflammatory cascade in human arthritis [13,16]; while COX2 level indicates the degree of inflammation in rheumatic arthritis (RA) synovial tissue [17]. It was found that CRF contributed significantly to PGE2 (a major COX-2 product) levels in a timeand dose-dependent manner in RA synovial tissue [13]. Furthermore, selective COX-2 inhibition completely prevented the production of CRF-induced PGE2 [13,14]. Thromboangiitis obliterans (TAO) is defined as a vasculitis [18]. Our recent study showed that in sodium laurate induced TAO model rats, plasma Ucn1 and PGE2 levels were elevated and the expressions of Ucn1 and COX-2 from rat femoral arteries were markedly increased; furthermore, Ucn1 application aggravated vasculitis and augmented COX-2 and PGE2 expression (original article accepted by Br. J. Phar-
484
R. Zhang, S. Li / Biochemical and Biophysical Research Communications 382 (2009) 483–485
macol.). In addition, our present data demonstrated that Ucn1 exerted a pro-inflammatory function by augmenting COX-2 and PGE2 expression in LPS-induced rat aortic endothelial cells (unpublished data). Recently, COX-2 pathway is involved in regulation of Ucnmediated pro-inflammatory cytokine productions [14,15]. Macrophages are targets of CRF family peptides [19–21]. In LPS-activated macrophages, CRF, Ucn1 and Ucn2 transiently suppressed the release of TNF-a while enhanced COX-2 expression and PGE2 release [14]. COX-2 inhibitor application demonstrated COX-2 and PGE2 were responsible for CRF family peptides-induced suppression of TNF-a release [14]. Furthermore, COX-2 pathway was found to be involved in regulation of Ucn-increased IL-6 production in rat aortic smooth muscle cells [15]. Taken together, CRF family peptides may participate in the pathophysiology of many inflammatory conditions via COX-2 pathway.
NF-jB activation [37]; while Ucn2 has pro-inflammatory effects in human intestinal cells by phosphorylation of NF-jB and degradation of IjBa [38]. Therefore, converging lines of evidence strongly support the relationship between CRF family peptides and COX-2 in signal transduction pathways. Recently, reports demonstrate that CRF family peptides and COX-2 share similar signal transduction pathways under inflammatory conditions [13,14]. In LPS-activated macrophages, the effect of CRF family peptides on COX-2 expression was mediated via PI3K and p38MAPK [14]. In RA synovial tissue, COX-2-dependent PGE2 production by CRF was confirmed to be due to the transcriptional activation of CREB/ATF [13]. Moreover, the stimulatory effects of both CRF and PGE2 on gene transcription have been shown to be mediated through cAMP/PKA/CREB dependent activation [13,39,40]. Thus, all these evidences may partially reveal the intrinsic relationship between CRF family peptides and COX-2 in inflammation.
CRF receptors and COX-2 Conclusion CRF has been reported to induce COX-2 expression in many tissues, such as RA synovial tissue [13] and human fetal membrane [22]. As CRF has 10-fold higher affinity for CRFR1 than for CRFR2 [2,3], the above COX-2 expression might be mediated by CRFR1. This was further confirmed by our recent study (original article accepted by Br. J. Pharmacol.). In sodium laurate induced TAO model rats, Ucn1-mediated COX-2 and PGE2 expression could be abolished by CRFR1 antagonist, NBI-27914 while CRFR2 antagonist, antisauvagine-30, could not. On the other hand, CRFR2 are also involved in COX-2 expression [14,15]. Kageyama et al. reported that in rat aortic smooth muscle cells, Ucn1 and Ucn2 induced the expression of COX-2 in a time- and dose-dependent manner via CRFR2 [15]. However, in LPS-activated macrophages, CRF, Ucn1 and Ucn2 transiently increased COX-2 and PGE2 synthesis [14]. For CRF having much higher affinity for CRFR1 while Ucn2 being selective for CRFR2 [2,3], the above effects were mediated by both CRFR1 and CRFR2. Furthermore, both CRFR1 antagonist a-helicalCRF and CRFR2 antagonist anti-sauvagine-30 blocked the effect of the neuropeptides on PGE2 release [14]. Taken together, all these evidences suggest that both CRFR1 and CRFR2 activations could increase COX-2 expression. However, recently, Gao et al. reported that CRF family peptides acted on CRFR1 and CRFR2 to exert different effects on COX-2 production in cultured human placental trophoblasts [23]. Placental trophoblasts expressed both CRFR1 and CRFR2 [23,24]. Treatment of cultured human placental trophoblast cells with exogenous CRF and Ucn1 showed an increase of COX-2 expression while Ucn2 or Ucn3 decreased COX-2 expression. Moreover, CRFR1 antagonist Antalarmin reduced COX-2 expression whereas CRFR2 antagonist astressin2b increased COX-2 expression [23]. Signaling networks between CRF family peptides and COX-2 Lots of evidences suggest the potential signaling networks between CRF family peptides and COX-2 [25–38]. On the one hand, the effects of CRF family peptides are mediated by two high-affinity receptors CRFR1 and CRFR2, both of which are Gsa/adenylyl cyclase/cAMP-coupled G-protein coupled receptors [25]. In addition, mitogen-activated protein kinases (MAPKs), Akt and nuclear factor kappa B (NF-jB) have been implicated as key signaling intermediates downstream of CRF receptors activation [26–31]. On the other hand, the expression of COX-2 is regulated by MAPKs [32–34], Akt [35] and several transcription factors including the cAMP response element binding (CREB), activating transcription factor (ATF) and NF-jB [35,36]. Furthermore, COX-2 is now considered to be NFjB regulated inflammatory genes which can be induced after
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