Regulation of cell migration and inflammation by ceramide 1-phosphate

Biochimica et Biophysica Acta 1861 (2016) 402–409

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Review

Regulation of cell migration and inflammation by ceramide 1-phosphate Natalia Presa a, Ana Gomez-Larrauri b, Io-Guané Rivera a, Marta Ordoñez a, Miguel Trueba a, Antonio Gomez-Muñoz a,⁎ a b

Department of Biochemistry and Molecular Biology, Faculty of Science and Technology, University of the Basque Country (UPV/EHU), P.O. Box 644, 48080 Bilbao, Spain Department of Pneumology, University Hospital of Araba, C/Jose Atxotegi, s/n, 01009 Vitoria-Gasteiz (Alava-Araba), Spain

a r t i c l e

i n f o

Article history: Received 24 September 2015 Received in revised form 5 February 2016 Accepted 8 February 2016 Available online 11 February 2016 Keywords: Cell migration Ceramides Ceramide 1-phosphate Inflammation Sphingolipids

a b s t r a c t Ceramide 1-phosphate (C1P) is a bioactive sphingolipid metabolite first shown to regulate cell growth and death. Subsequent studies revealed that C1P was a potent stimulator of cytosolic phospholipase A2 (cPLA2) with ensuing release of arachidonic acid and prostaglandin biosynthesis. The latter findings placed C1P on the list of proinflammatory metabolites. More recently, C1P was found to potently stimulate cell migration, an action that is associated to diverse physiological effects, as well as to inflammatory responses and tumor dissemination. The implication of C1P in inflammation has gained further interest in the last few years due to the discovery that it can exert anti-inflammatory actions in some cell types and tissues. In particular, C1P has been demonstrated to inhibit pro-inflammatory cytokine release and blockade of the pro-inflammatory transcription factor NF-κB in some cell types, as well as to reduce airway inflammation and lung emphysema. The present review is focused on novel aspects of C1P regulation of cell migration and the impact of C1P as novel anti-inflammatory agent. Gloss: Ceramide 1-phosphate (C1P) is a phosphosphingolipid with potent biological activities. It promotes cell growth and survival, and is a key regulator of cell migration. Both C1P and the enzyme that catalyzes its biosynthesis, ceramide kinase, are implicated in inflammatory responses. Although C1P has pro-inflammatory properties, it reduces pulmonary emphysema and exerts anti-inflammatory actions in the lung. Synthetic C1P analogs may be promising tools to treat lung inflammation. © 2016 Elsevier B.V. All rights reserved.

1. Introduction Sphingolipids play critical roles in eukaryotic cells. They are fundamental for cell membrane architecture, and some of them are regulators of key physiologic cell functions. In particular, the simple sphingolipid metabolites, ceramides, sphingosine 1-phosphate (S1P) and ceramide 1-phosphate (C1P) are involved in the regulation of cell proliferation, survival, embryo development, organogenesis, autophagy, immune cell trafficking, or steroidogenesis [1–13]. Additionally, these sphingolipids are implicated in a variety of pathological processes, especially those that are associated to inflammatory diseases. Specifically, ceramides induce cell cycle arrest, promote apoptosis, and are potent pro-inflammatory agents in a variety of cell types (reviewed in [14– 16]). By contrast, S1P and C1P stimulate cell proliferation, promote

Abbreviations: AA, arachidonic acid; Akt (PKB), protein kinase; BMDM, bone marrowderived macrophages; CerK, ceramide kinase; C1P, ceramide 1-phosphate; cPLA2, calcium-dependent cytosolic phospholipase 2; ERK, extracellularly regulated kinases; GLUT, glucose transporter; MCP-1, monocyte chemoattractant protein-1; iNOS, inducible nitric oxide synthase; PA, phosphatidic acid; PI3K, phosphatidylinositol 3-kinase; PKC, protein kinase C; PTX, pertussis toxin; ROS, reactive oxygen species; SMase, sphingomyelinase; SphK, sphingosine kinase; SPT, serine palmitoyl transferase; S1P, sphingosine1-phosphate. ⁎ Corresponding author. E-mail address: [email protected] (A. Gomez-Muñoz).

http://dx.doi.org/10.1016/j.bbalip.2016.02.007 1388-1981/© 2016 Elsevier B.V. All rights reserved.

cell survival and can exert pro- or anti-inflammatory functions depending upon the cell type in which they are generated [3,16,17]. Initial studies conducted to elucidate the role of these sphingolipids in cell biology were not easy at the time mainly because ceramide, sphingosine and their phosphorylated forms are all interconvertible [18,19]. In particular, ceramides can be acted upon by ceramidases and be converted to sphingosine, which can then be phosphorylated to form S1P by the action of specific kinases (sphingosine kinases 1 and 2). S1P can, in turn, be dephosphorylated by various types of phosphatases, including lipid phosphate phosphatases [20,21] to form sphingosine, which can then be converted back to ceramide by the action of ceramide synthase activities (reviewed in [22]). First, it was observed that ceramides were able to inhibit at least some of the S1P actions in cells. Specifically, ceramides blocked the stimulation of DNA synthesis by S1P and inhibited S1Pactivated phospholipase D (PLD) in fibroblasts [18]. Subsequently, S1P was shown to inhibit ceramide-induced cell death in human histiocytic lymphoma U937 cells and Jurkat cells [23]. These were probably the first reports leading to the concept of the sphingolipid rheostat. Alternatively, ceramide can be directly phosphorylated by ceramide kinase (CerK) to form C1P. The biosynthesis of C1P takes place in the Golgi apparatus where CerK is also located (Fig. 1). CerK uses ceramide that is transported from the endoplasmic reticulum by a specific ceramide transport protein (CERT) [24,25]. CerK also resides in the cytosol, nucleus, and the

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Fig. 1. Biosynthesis and cell distribution of ceramide 1-phosphate (C1P). Ceramides generated in the endoplasmic reticulum (ER) are transported to the Golgi by a ceramide transfer protein (CERT). Ceramides can be phosphorylated by a ceramide kinase (CERK) that resides in the Golgi to generate C1P. A C1P transfer protein (CPTP) will then transport C1P to the plasma membrane (PM) and probably other organelles.

plasma membrane of cells [26], and is the only enzyme so far described for C1P biosynthesis in mammalian cells. Alternatively, C1P might be generated by other pathways. For example, the transfer of a fatty acyl chain to S1P, or the degradation of sphingomyelin (SM) by D-type phospholipases would render C1P directly [27]. However, neither of these enzymes has so far been identified in mammalian tissues, which contrasts with recent findings showing that mice lacking the CerK gene (CerK−/−) still have very high levels of C1P compared to wild type animals [28,29]. Although the existence of a S1P acyl transferase has so far not been reported in any living organism (or microorganism), high levels of SMase D can be found in the venom of some arthropods including some spiders of the gender Loxosceles (i.e., the brown recluse spider or the violin or fiddleback spider) [30–32]. Also, SMase D is a major component of the toxins of some bacteria including Corynebacterium tuberculosis, Archanobacterium haemoliticum, or Vibrio damsela (reviewed in [27]). A major product of SMase D activity is C1P [33]. However, this enzyme has recently been shown to also catalyze a transphosphatidylation rather than a hydrolytic reaction in vivo thereby forming cyclic ceramide (1,3) phosphate instead of C1P, from SM [34]. Once generated, C1P can be transported to the plasma membrane and probably other organelles by a specific ceramide phosphate transfer protein (CPTP) that resides in the cytosol and can travel to the transGolgi network to bind C1P [26] (Fig. 1). The first biological activity demonstrated for C1P was stimulation of cell proliferation [35]. The molecular mechanisms involved in this process included activation of classical mitogenic kinases such as extracellularly regulated kinases 1-2 (ERK1-2), c-Jun N-terminal kinase (JNK), p38, mammalian target of rapamycin (mTOR); phosphatidylinositol 3kinase (PI3K), Akt, or protein kinase C-α [36–41]. Also, small increases in reactive oxygen species (ROS), activation of the ROCK/RhoA pathway, and up-regulation of retinoblastoma were implicated in C1P-stimulated macrophage or myoblast proliferation [38,42]. In addition, short-chain C1P analogs potently stimulated calcium mobilization from intracellular stores in calf pulmonary artery endothelial cells [43] and Jurkat T-cells [44]. Moreover, CerK was shown to be essential for proliferation of human lung adenocarcinoma A549 cells [45], MCF-7 breast cancer cells and NCI-H358 lung cancer cells [46], renal messangial cells and

fibroblasts [47], and human neuroblastoma cells [40]. Subsequent studies uncovered a role for CerK and C1P in cell survival. Specifically, C1P was able to inhibit apoptosis in different cell types. The molecular mechanisms involved in this action include inhibition of ceramide formation through blockade of acid sphingomyelinase (A-SMase) [48] or serine palmitoyl transferase (SPT) activities [49], as well as activation of the PI3K/Akt pathway [50] and up-regulation of the inducible form of nitric oxide synthase (iNOS) [51]. Noteworthy, C1P was also found to be a key mediator of retina photoreceptor proliferation, survival and differentiation [52]. In addition to regulating cell growth and survival, C1P has been shown to play a crucial role in the regulation of cell migration, and is a key player in the control of inflammatory responses (Table 1). Fig. 2 highlights the major biological functions elicited by C1P in mammalian cells. 1.1. Control of cell migration by ceramide 1-phosphate Cell migration is an essential physiological process that is critical at many stages of embryogenesis, organogenesis, wound healing, regeneration, or immune responses including inflammation. Uncontrolled inflammation, however, is detrimental for cells, and can lead to disease. Also, production of abnormal chemotactic signals may induce the migration of cells to inappropriate sites in the organism, thereby altering tissue homeostasis. For example, cell migration plays a critical role in chronic inflammatory diseases, such as asthma, multiple sclerosis, rheumatoid arthritis, or IBD (namely ulcerative colitis and Crohn's disease) [53,54]. Cell migration also contributes to tumor cell spreading or metastasis, for which cells acquire an invasive phenotype characterized by increased proteolytic activity and cell motility [55]. Noteworthy, upregulation of CerK or treatment with exogenous C1P potently enhanced migration and invasion of human pancreatic cancer cells, suggesting that the CerK/C1P axis is a key factor in pancreatic cancer cell dissemination [56]. Cell migration is also important in vascular diseases including atherosclerosis and other vascular dysregulations [57–60]. The molecular mechanisms involved in the regulation of cell migration are not completely understood. However, some of the signaling or metabolic pathways that are involved in this process have been

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Table 1 Major biological effects of ceramide 1-phosphate. C2-, acetyl; C6-, hexanoyl; C8-, octanoyl; C12-, lauroyl; C16-, palmitoyl; C18-, stearoyl; C(nm)-, natural mixture of C1P from bovine brain (the major fatty acids would be stearic and nervonic, and to a lesser extent lignoceric, behenic, palmitic, and arachidic acids (Sigma-Aldrich, St. Louis, MO). Biological effect

Cell type/tissue

C1P concentration range

C1P N-acyl chain length

C1P receptor dependent

References

Stimulation of cell proliferation

Rat-1, C2C12, VSMCs BMDM A549, MCF-7, NCI-H358 Rat retinal neurons

1–50 μM

C2-, C8-, C16-, C(nm)-

No

[35–42,45,46,52]

Endogenous C1P 1–10 μM 10–50 μM

–

C2-, C8-, C(nm)-

No

[48–52]

1–10 μM 20–40 μM

C8C8-, C16-, C(nm)-

5–30 μM 1–10 μM 20–100 μM 1–2 μM 0.1–1 μM 0.1–50 μM

C16-

Inhibition of apoptosis

Induction of cell migration or invasion

Regulation of inflammation

NR8383 BMDM Rat retinal neurons VSMC, RAW264.7, J774A.1, THP-1, 3T3-L1, MSC, EC, VSEL, PANC-1, MIA PaCa-2 BMMNC HSC ARMS, ERMS, HUVEC VEC

Stimulation of phagocytosis

A549, MEFs, L929, C12, RAW264.7, NR8383, J774A.1, BEAS-2B, human neutrophils, HEK293, Keratinocytes SH-SY5Y COS-1, PMNs

Degranulation

RBL-2H3

Obesity and insulin resistance Stimulation of glucose uptake Calcium mobilization

CERK−/− mice RAW264.7, C2C12 Jurkat human leukemia T-cells, CPAE

C8-

[39,56,62,63,75–77,79,80,83,84]

Yes/?

C12-, C18C12-, C18C2-, C6-, C8-, C12-, C16-, C18-

[17,33,87–89,92,93,99,124–127]

No/? –

Endogenous C1P Endogenous C1P – 15 μM 0.5–1 μM

– C16C8-

0.6 nM

C2-

identified. These include up-regulation of protein kinase C (PKC), glycogen synthase 3-betta (GSK3-β), AMP dependent-kinase (AMPK), the par1-related proteins MARCKS (myristoylated alanine-rich protein kinase C substrate), LKB1 and the subsequent activation of Rho GTPases, phosphoinositide 3-kinase (PI3K)/phosphatase and tensin homolog (PTEN)/Akt/mammalian target of rapamycin (mTOR), Ras/Raf/MEK/extracellular signal-regulated kinase (ERK), or Notch [61–68]. Also, the Wnt signaling pathway plays a critical role in cell migration/invasion

?

–

[95,96] [94]

? Yes ?

[82] [85] [43,44]

processes [61,69–73]. Interestingly, some of these pathways have been shown to be regulated by bioactive sphingolipids. In particular, C1P can induce cell migration in different cell types, including macrophages, myoblasts, or 3T3 pre-adipocytes [62,63]. Initially, stimulation of cell migration was observed in macrophages stimulated with exogenous C1P, whereas intracellularly generated C1P failed to promote migration in these cells. These observations led to identification of a specific receptor for C1P. This receptor was unable to bind other sphingolipids

Fig. 2. Biological functions regulated by ceramide 1-phosphate. Endogenously generated C1P stimulates cell proliferation, promotes phagocytosis and inflammation, inhibits apoptosis, and can participate in the stimulation of cell migration. Exogenous C1P promotes cell migration and invasion, stimulates glucose uptake and reduces inflammation. Some of the extracellular actions of C1P including stimulation of cell migration/invasion and glucose uptake are mediated through ligation of C1P with a putative Gi protein-coupled plasma membrane receptor.

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including short- or long-chain ceramides, S1P, or SM. However, relatively high concentrations of C1P (in the range 5–30 μM) were needed to activate the receptor indicating that it was of low affinity (Table 1). The dissociation constant for binding of C1P to its receptor was about 7.7 μM, with a maximum binding capacity of about 1270 pmol/mg protein [62]. To further characterize the C1P receptor studies were conducted using pertussis toxin (PTX), which is a potent inhibitor of Gi proteins, and is often used to study Gi protein-coupled receptors. PTX completely blocked C1P-stimulated cell migration, suggesting coupling of the C1P receptor to a Gi protein. Further studies using the non-hydrolysable analog GTPγS showed blockade of C1P binding to isolated cell membranes. Moreover, C1P stimulated radiolabeled GTPγS binding to cell membranes and this effect was blocked by non-hydrolysable GDPγS, thereby confirming coupling of the C1P receptors to G proteins [62]. The stimulation of C1P receptors is physiologically possible as C1P is found extracellularly. In fact, the concentration of C1P in plasma or serum of mice has been reported by different groups. Plasma concentrations of C1P were shown to vary according to the nutritional state of the organism [74], and have been reported to be as high as 20 μM [29]. Major sources for C1P are macrophages, and leaky damaged cells [28,75,76]. More recently, ligation of C1P to its receptor induced rapid phosphorylation of ERK1-2, c-JNK, and Akt, causing activation of these kinases and release of MCP-1 [63]. Inhibition of any of these kinases abrogated C1Pstimulated MCP-1 release and macrophage migration. However, although C1P stimulated c-JNK, inhibition of this kinase had no effect on C1P-stimulated macrophage migration. C1P also stimulated the DNA binding activity of NF-κB, and down-regulation of this transcription factor resulted in inhibition of MCP-1 release and macrophage migration. It was concluded that MEK/ERK1-2, PI3-K/PKB (Akt) and NF-κB are essential pathways for regulation of MCP-1 release and the subsequent stimulation of cell migration by C1P. MCP-1 was also implicated in 3T3 preadipocyte and human THP-1 monocyte migration by C1P [63]. The chemotactic effect of C1P has now been confirmed by other groups. Specifically, Ratajczak and co-workers [76] found that C1P potently stimulated homing of hematopoietic stem/progenitor cells to the bone marrow, and that C1P is a major regulator of multipotent stromal cell and endothelial progenitor cell migration. The same authors also reported that C1P activated MAPK44/42 (ERK1/2), which are kinases involved in stimulation of cell migration, and that PTX blocked this action suggesting that the chemotactic effect of C1P might be mediated by a Gi protein-coupled receptor [75], in agreement with previous work [62, 63]. Moreover, C1P and S1P were shown to regulate trafficking of normal and malignant cells and that both agonists were pro-metastatic factors in human rhabdomyosarcoma suggesting a relevant role of C1P in tissue regeneration and tumor dissemination [75,77–79]. In agreement with the above observations, extracellular C1P was found to interact with annexin a2-p11 protein complex to elicit endothelial cell migration [80]. This protein complex, which is expressed in vascular endothelial cells, serves as a receptor platform for multiple proteins that differentially regulate the wound healing process, such as fibrinolysis and vascular invasion through the extracellular matrix [80]. In line with the latter observations, Wijesinghe and co-workers recently reported that C1P is required for migration of fibroblasts into wound sites, thereby emphasizing the role of C1P in controlling cell migration and the wound healing processes [81]. Ablation of CerK resulted in decreased levels of intracellular C1P, inhibition of the ability of fibroblasts to release AA and impaired fibroblast migration [81] suggesting that C1P generated intracellularly is also important for regulation of cell migration. The latter findings are consistent with previous studies using bone marrow-derived macrophages, in which CerK deficiency prevented infiltration of macrophages into adipose tissue [82]. However, these latter studies using murine fibroblasts or macrophages did not address whether intracellularly generated C1P might be released into the extracellular environment to stimulate cell migration through receptor-mediated mechanisms in an autocrine or paracrine manner. Noteworthy, C1P-stimulated cell migration is not restricted to

405

vertebrates. In fact, C1P was able to potently stimulate migration of primordial germ cells to the gonad in Drosophila, an action that involved participation of WntD (Wnt inhibitor of Dorsal, CG8458, formerly annotated Wnt8) in the control of C1P production by CerK [83]. The latter work is consistent with a model in which the activity of lipid phosphate phosphatases (LPPs), formerly known as phosphatidate phosphohydrolase-2 (PAP-2) that are able to dephosphorylate C1P [20], create a concentration gradient of C1P allowing primordial germ cell migration [83]. Another key observation concerning the regulation of cell migration by C1P was that phosphatidic acid (PA), which is a glycerophospholipid structurally related to C1P, was able to modulate C1P-stimulated macrophage migration. Although PA has been shown to be chemotactic for some cell types, it did not affect macrophage migration significantly by its own. However, it potently inhibited C1P-stimulated macrophage migration [84]. The inhibitory effect of PA involved its interaction with the C1P receptor, displacement of C1P from its membrane binding site, and inhibition of ERK1-2 phosphorylation thereby leading to blockade of cell migration [84]. In addition, in situ formation of PA by incubation of macrophages with exogenous bacterial phospholipase D to generate PA at the plasma membrane caused potent inhibition of ERK1-2 and blocked C1P-stimulated cell migration [84]. The latter findings suggest that PA is a natural antagonist of the C1P receptor and that is an essential factor for regulating macrophage migration. Another important observation was that C1P was able to stimulate glucose uptake and ATP production in macrophages [85], which are actions consistent with a recent report showing that glucose uptake facilitates chemotaxis in human peripheral blood cells [86]. The mechanism by which C1P stimulated glucose uptake in macrophages involved interaction of C1P with its plasma membrane receptor, activation of the PI3K/Akt pathway, and translocation of the glucose transporter GLUT3 from the cytosol to the cell membrane [85]. 1.2. Role of ceramide kinase/C1P in inflammation The first report implicating C1P in inflammatory responses was by the Chalfant laboratory. C1P was first shown to stimulate arachidonic acid (AA) release and the subsequent production of pro-inflammatory eicosanoids including prostaglandins in A549 lung adenocarcinoma cells [33]. This action involved translocation of group IV cytosolic phospholipase A2 (cPLA2) from the cytosolic compartment to intracellular membranes [87,88], and direct activation of the enzyme by C1P [89– 91]. Other studies by the Chalfant group revealed that C1P is a positive allosteric activator of cPLA2 [92], and that the extent of activation of this phospholipase was dependent upon the length of the N-linked acyl chain of C1P. Specifically, only C1P with acyl chains longer than 6 carbons were able to activate cPLA2 in vitro [93]. C1P stimulation of cPLA2 involved the recruitment of this cytosolic enzyme to membrane compartments [87]. The latter studies suggested that C1P generated intracellularly by the action of CerK exerted pro-inflammatory actions. In fact, genetic ablation of CerK in mice caused significant decreases in multiple C1P species and potently reduced the levels of multiple proinflammatory eicosanoids [29]. A second mechanism by which C1P stimulates cPLA2 includes activation of protein kinase C. In particular, downregulation of PKC by prolonged incubation with phorbol-12myristate-13-acetate, or pharmacological inhibition of the enzyme activity, substantially blocked C1P-stimulated release of AA in murine fibroblasts [88]. Eicosanoid production is initiated by cPLA2 at the Golgi apparatus, where CPTP also resides. Interestingly, depletion of this C1P transport protein, which is the only transporter for C1P so far described in mammalian cells, increased C1P levels in the Golgi and simultaneously decreased C1P in the plasma membrane resulting in cPLA2 activation, release of AA and generation of pro-inflammatory eicosanoids [26]. Other inflammatory processes in which C1P was implicated include mast cell degranulation [94], and stimulation of phagocytosis in neutrophils [95,96]. Moreover, wild type mice fed a high fat diet expressed

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high levels of the pro-inflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) [97,98]. However, these actions were suppressed in CerK (−/−) animals [82]. Also, CerK (−/−) mice showed decreased MCP-1/CCR2 (C-C motif chemokine receptor-2) signaling in macrophages infiltrating the adipose tissue, which resulted in suppression of inflammation in adipocytes, an action that would support attenuation of obesity and diabetes [82]. Knockdown of CerK using specific siRNA to silence the cerk gene was also shown to inhibit NADPH oxidase (NOX) activation and eicosanoid production in neuroblastoma cells thereby implicating this enzyme in oxidative stress-induced inflammation in the brain [99]. Although the pro-inflammatory properties of intracellular C1P are well established, as discussed above, increasing experimental evidence indicates that C1P can also exert anti-inflammatory actions in some particular cell types or tissues. Many of the anti-inflammatory effects of C1P include blockade or counteraction of ceramide-induced inflammatory responses. In fact, a vast number of reports show that ceramides mediate or promote inflammation in vitro as well as in animal models. In particular, some pro-inflammatory cytokines such as TNF-α, interferon-γ, interleukins (IL) including IL-1β [100], or platelet-activating factor (PAF) [101] have been shown to potently stimulate SMase activity leading to ceramide accumulation and promotion of inflammation in different cell types [102,103]. A major pro-inflammatory action of ceramide is activation of the transcription factor NF-κB, which is ubiquitously expressed in mammalian cells [104]. NF-κB can regulate the expression of a large number of genes in mammalian cells, leading to up-regulation of many other genes involved in inflammatory responses. Some of these pro-inflammatory genes encode cytokines such as IL-1β, IL-6, or IL-8, chemokines such as MCP-1, and pro-inflammatory enzymes that are involved in the synthesis of pro-inflammatory eicosanoids including cyclooxygenase-2 (COX-2) [104,105]. In addition, ceramides have been involved in the development of type II diabetes linked to obesity [106,107], and there is a strong association between diabetes and inflammation [108–115]. Moreover, ceramides are also important in lung pathophysiology. Specifically, ceramides have been implicated in the pathology of asthma, chronic obstructive pulmonary disease (COPD) and pulmonary fibrosis [116,117], and have been shown to play relevant roles in pulmonary infections [118]. Also, it was reported that A-SMase-derived ceramides mediate PAF-induced pulmonary edema [101], and that this enzyme activity is involved in the pathology of cystic fibrosis [117]. In addition, emphysema caused by exposure to cigarette smoke, was related to increased levels of ceramides in human and murine lungs, or in alveolar macrophages and primary endothelial and epithelial lung cells [119–123]. Therefore, ceramides are well established pro-inflammatory mediators, and so, this sphingolipid or the enzymes responsible for its biosynthesis are relevant targets for treatment of inflammatory responses or inflammation-associated diseases. In this connection, one of the initial anti-inflammatory actions of C1P might be inhibition of stimulated ceramide production, an action that was reported to occur in alveolar macrophages through blockade of SPT, A-SMase and N-SMase and that was associated to the antiapoptotic effect of C1P [49]. Whether this inhibitory action of C1P might be related to a possible blockade of pro-inflammatory cytokine production is unknown at the present time. A key observation showing that C1P is anti-inflammatory in lung tissue was the inhibition of cigarette smoke-induced airway inflammation. C1P, or its short-chain analog N-octanoyl (C8)-C1P, potently blocked the pro-inflammatory effects of ceramides in the lung. Specifically, relatively short-term exposure (three days) of mice to cigarette smoke induced increases of leukocytes (neutrophils and macrophages), and increased the levels of the pro-inflammatory cytokines IL-1β, IL-6, keratinocyte chemoattractant, and macrophage inflammatory protein-2 in bronchoalveolar lavage fluid in mice, and all of these effects were potently attenuated by treatment with C1P or C8-C1P [124]. Also, leukocyte infiltration in pulmonary tissue was potently reduced by C1P. Of interest, these effects of C1P were observed before and after cigarette smoke exposure,

suggesting that exogenous C1P can prevent as well as treat lung inflammation [124]. In addition, animals exposed to cigarette smoke for seven months showed foci of emphysema disseminated throughout the lung parenchyma, and oral treatment with C1P or C8-C1P for the last three months potently reduced lung emphysema. This effect was accompanied by reduced number of macrophages and neutrophils in bronchoalveolar lavage fluid as well as decreased levels of pro-inflammatory cytokines [124]. The anti-inflammatory effects of C1P were also associated to inhibition of the expression of N-SMase 2 NF-κB, matrix metalloprotease-9, MYD88 and TNF-receptor-associated factor-2 (TRAF-2) [124]. C1P also potently inhibited the production of TNF-α that was stimulated by lipopolysaccharide (LPS) [125,126], decreased LPS-activated transcription of NF-κB, and abrogated the production of IL-6, IL-8 and IL-1β in HEK 293 TLR4-expressing cells as well as human peripheral blood mononuclear cells [126]. In addition, C1P was shown to be a potent inhibitor of TNF-α converting enzyme (TACE) [126], thereby emphasizing the anti-inflammatory action of C1P. Also of interest, C1P has been recently shown to elicit antimicrobial activity against Staphylococcus aureus through up-regulation of human defensins hBD2 and hBD3 [127]. Up to date, no report has ever addressed whether any of the anti-inflammatory effects of exogenous C1P might be mediated through activation of the putative C1P receptor. It should also be noted that the C1P analogs PCERA-1 and ONO-SM362 inhibited the production of TNF-α and induced the release of antiinflammatory IL-10 in macrophages [128–130]. These antiinflammatory effects of PCERA-1 were unaffected by C1P [131]. Also, PCERA-1 potently inhibited cPLA2 activity and the subsequent formation of pro-inflammatory prostaglandins in LPS-stimulated macrophages [132]. The latter findings suggest that PCERA-1, ONO-SM-362, and possibly other C1P analogs, may potentially be relevant for developing new strategies for treatment of inflammatory responses. 2. Concluding remarks It has become clear that C1P modulates inflammatory responses. Both intra and extracellular actions of C1P are probably necessary to elicit its pro-inflammatory effects, namely because cPLA2 activation requires direct interaction of C1P with the enzyme, whereas macrophage migration relies on the interaction of C1P with its plasma membrane receptor. The pro-inflammatory actions of intracellular C1P are well documented for different biological settings and cell types. However, the recent observations that exogenous C1P can also promote antiinflammatory responses add complexity to the role of C1P in inflammation. Of particular interest is the fact that exogenous C1P decreases the levels of pro-inflammatory ceramides by inhibiting acidic or neutral SMases, inhibits NF-kB, MMP-9, MYD88 and TRAF-2 expression or activity, blocks pro-inflammatory cytokine release and reduces immune cell infiltration and emphysema in mouse or human lungs exposed to cigarette smoke. Moreover, C1P protects against pulmonary bacterial infection thereby contributing to the reduction of lung inflammation. Needless to say that there is enormous scientific and clinical interest to understand the mechanisms by which C1P exerts its antiinflammatory effects as this might help to develop novel therapeutic strategies to control inflammation-related lung diseases such as asthma, COPD, or cystic fibrosis. Inflammation and cell migration are also crucial factors in cardiovascular diseases, obesity, tumorigenesis and tumor progression. Understanding C1P biology in both normal and inflamed tissue will definitely help to envision new ways for therapy of acute and chronic inflammatory diseases, as well as inflammation-related illnesses such as atherosclerosis, obesity and cancer. Transparency document The Transparency document associated with this article can be found, in the online version.

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Acknowledgments Work in AGM laboratory is supported by “Departamento de Educación, Universidades e Investigación del Gobierno Vasco (GazteizVitoria, Basque Country)” grant number IT-705-13. We are also grateful to “Unidad de formación e investigación (UFI) 11/20 (UPV/EHU)” for technical support.

[27]

[28]

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