The nucleotide adenosine triphosphate (ATP) has long been known to drive and participate in countless intracellular processes. Extracellular ATP and its metabolite adenosine have also been shown to exert a variety of effects on nearly every cell type in human skin. Knowledge of the sources and effects of extracellular ATP in human skin may help shape new therapies for skin injury, inflammation, and numerous other cutaneous disorders.
Objective:
The objective of this review is to introduce the reader to current knowledge regarding the sources and effects of extracellular ATP in human skin and to outline areas in which further research is necessary to clarify the nature and mechanism of these effects.
Conclusion:
Extracellular ATP seems to play a direct role in triggering skin inflammatory, regenerative, and fibrotic responses to mechanical injury, an indirect role in melanocyte proliferation and apoptosis, and a complex role in Langerhans cell-directed adaptive immunity.
Get full access to this article
View all access options for this article.
References
1.
DruryANSzent-GyörgyiA. The physiological activity of adenine compounds with special reference to their action upon the mammalian heart. J Physiol (Lond)1929; 68:213–237.
2.
HoltonP. The liberation of adenosine triphosphate on antidromic stimulation of sensory nerves. J Physiol (Lond)1959; 145:494–504.
3.
BurntockGCampbellGSatchellD. Evidence that adenosine triphosphate or a related nucleotide is the transmitter substance released by non-adrenergic inhibitory nerves in the gut. Br J Pharmacol1970; 40:668–688.
4.
BurnstockG. A basis for distinguishing two types of purinergic receptor. In: StraubRWBolisL, eds. Cell Membrane Receptors for Drugs and Hormones: A Multidisciplinary Approach. New York: Raven Press, 1978; pp 107–118.
5.
BurnstockGKennedyC. Is there a basis for distinguishing two types of P2-purinoceptor?Gen Pharmacol1985; 16:433–440.
6.
AbbracchioMPBurnstockG. Purinoceptors: Are there families of P2X and P2Y purinoceptors?Pharmacol Ther1994; 64:445–475.
7.
SurprenantARassendrenFKawashimaE. The cytolytic P2Z receptor for extracellular ATP identified as a P2X receptor (P2X7). Science1996; 272:735–738.
8.
BurnstockGRalevicV. New insights into the local regulation of blood flow by perivascular nerves and endothelium. Br J Plast Surg1994; 47:527–543.
9.
ErlingeD. Extracellular ATP: A growth factor for vascular smooth muscle cells. Gen Pharmacol1998; 31:1–8.
10.
HollopeterGJantzenHMVincentD. Identification of the platelet ADP receptor targeted by antithrombotic drugs. Nature2001; 409:202–207.
11.
WangLKarlssonLMosesS. P2 receptor expression profiles in human vascular smooth muscle and endothelial cells. J Cardiovasc Pharmacol2002; 40:841–853.
12.
NinomiyaHOtaniHLuK. Complementary role of extracellular ATP and adenosine in ischemic preconditioning in the rat heart. Am J Physiol Heart Circ Physiol2002; 282:H1810–H1820.
13.
PellegASchulmanES. Adenosine 5′-triphosphate axis in obstructive airway diseases. Am J Ther2002; 9:454–464.
14.
ReisinILPratAGAbrahamEH. The cystic fibrosis transmembrane conductance regulator is a dual ATP and chloride channel. J Biol Chem1994; 26932:20584–20591.
15.
SchulmanESGlaumMCPostT. ATP modulates anti-IgE-induced release of histamine from human lung mast cells. Am J Respir Cell Mol Biol1999; 20:530–537.
16.
MichoudMCNapolitanoGMaghniK. Effects of extracellular triphosphate nucleotides and nucleosides on airway smooth muscle cell proliferation. Am J Respir Cell Mol Biol2002; 27:732–738.
17.
FernandesTRde OliveiraDSSuzuki-KemmelmeierF. Inhibition by extracellular ATP of organic anion transport in the perfused rat liver. Eur J Pharmacol2002; 454:225–234.
18.
FeranchakAPFitzJG. Adenosine triphosphate release and purinergic regulation of cholangiocyte transport. Semin Liver Dis2002;22:251–262.
19.
BurnstockG. Purinergic signalling in gut. In: AbbracchioMPWilliamsM, Eds. Handbook of experimental pharmacology II: Purinergic and pyrimidinergic signalling II; cardiovascular, respirator)', immune, metabolic and gastrointestinal tract function, Vol. 151. Berlin: Springer-Verlag, 2001; pp 141–238.
20.
BurnstockG. Purine-mediated signalling in pain and visceral perception. Trends Pharmacol Sci2001; 22:182–188.
21.
JacksonEK. P1 and P2 receptors in the renal system. In: AbbracchioMPWilliamsM, eds. Handbook of experimental pharmacology II: Purinergic and pyrimidinergic signalling II; cardiovascular, respiratory, immune, metabolic and gastrointestinal tract function, Vol 151. Berlin: Springer-Verlag, 2001; pp 33–71.
22.
BurnstockG. Purinergic signalling in the lower urinary tract. In: AbbracchioMPWilliamsM, eds. Handbook of experimental pharmacology I: Purinergic and pyrimidinergic signalling I; molecular, nervous and urinogenitary system function, Vol. 151. Berlin: Springer-Verlag, 2001; pp 423–515.
23.
KribbenAFeldkampTHorbeltM. ATP protects, by way of receptor-mediated mechanisms, against hypoxia-induced injury in renal proximal tubules. J Lab Clin Med2003; 141:67–73.
24.
BagordaAGuerraLDi SoleF. Extracellular adenine nucleotides regulate Na+/H+ exchanger NHE3 activity in A6-NHE3 transfectants by a cAMP/PKA-dependent mechanism. J Membr Biol2002; 188:249–259.
25.
HarveyRASkennertonDENewgreenD. The contractile potency of adenosine triphosphate and ecto-adenosine triphosphatase activity in guinea pig detrusor and detrusor from patients with a stable, unstable or obstructed bladder. J Urol2002; 168:1235–1239.
26.
KnightDD'ArbeMLiangS. Regional differences in sympathetic purinergic transmission along the length of the mouse vas deferens. Synapse2003; 47:225–235.
27.
GürSÖztürkB. Altered relaxant responses to adenosine and adenosine 5′-triphosphate in the corpus cavernosum from men and rats with diabetes. Pharmacology2000; 60:105–112.
28.
RytenMDunnPMNearyJT. ATP regulates the differentiation of mammalian skeletal muscle by activation of a P2X5 receptor on satellite cells. J Cell Biol2002; 158:345–355.
29.
ColletCStrubeCCsernochL. Effects of extracellular ATP on freshly isolated mouse skeletal muscle cells during pre-natal and post-natal development. Pflugers Arch2002; 443:771–778.
30.
KimMSLeeJHaJ. ATP stimulates glucose transport through activation of P2 purinergic receptors in C(2)C(12) skeletal muscle cells. Arch Biochem Biophys2002; 401:205–214.
31.
HoebertzAMahendranSBurnstockG. ATP and UTP at low concentrations strongly inhibit bone formation by osteoblasts: A novel role for the P2Y2 receptor in bone remodeling. J Cell Biochem2002; 86:413–419.
32.
BuckleyKAHipskindRAGartlandA. Adenosine triphosphate stimulates human osteoclast activity via upregulation of osteoblast-expressed receptor activator of nuclear factor-kappaB ligand. Bone2002; 31:582–590.
33.
RapaportE. Involvement of elevated intracellular and extracellular ATP in the regulation of insulin secretion: Therapeutic targets in Non-Insulin-Dependent Diabetes Mellitus. Am J Ther1995; 2:283–289.
34.
WangCZNambaNGonoiT. Cloning and pharmacological characterization of a fourth P2X receptor subtype widely expressed in brain and peripheral tissues including various endocrine tissues. Biochem Biophys Res Commun1996; 220:196–202.
35.
MarsiglianteSEliaMGDi JesoB. Increase of [Ca(2+)](i) via activation of ATP receptors in PC-C13 rat thyroid cell line. Cell Signal2002; 14:61–67.
36.
TroadecJDThirionS. Multifaceted purinergic regulation of stimulus–secretion coupling in the neurohypophysis. Neuroendocrinol Lett2002; 23:273–280.
37.
StojilkovicSSKoshimizuT. Signaling by extracellular nucleotides in anterior pituitary cells. Trends Endocrinol Metab2001; 12:218–225.
38.
CourageotMPLepineSGiraudF. Extracellular ATP induces phosphatidylserine externalization earlier than nuclear apoptotic events in thymocytes. Ann N Y Acad Sci2002; 973:186–189.
39.
Di VirgilioFBoreaPAIllesP. P2 receptors meet the immune system. Trends Pharmacol Sci2001; 22:5–7.
40.
Di VirgilioFSoliniA. P2 receptors: New potential players in atherosclerosis. Br J Pharmacol2002; 135:831–842.
KharlamovAJonesSCKimDK. Suramin reduces infarct volume in a model of focal brain ischemia in rats. Exp Brain Res2002; 147:353–359.
43.
LabasiJMPetrushovaNDonovanC. Absence of the P2X7 receptor alters leukocyte function and attenuates an inflammatory response. J Immunol2002; 168:6436–6445.
44.
TrautTW. Physiological concentrations of purines and pyrimidines. Mol Cell Biochem1994; 140:1–22.
45.
LazarowskiERBoucherRC. UTP as an extracellular signaling molecule. News Physiol Sci2001; 16:1–5.
46.
RalevicVBurnstockG. Effects of purines and pyrimidines on the rat mesenteric arterial bed. Circ Res1991; 69:1583–1590.
47.
ReimerWJDixonSJ. Extracellular nucleotides elevate [Ca2+] in rat osteoblastic cells by interaction with two receptor subtypes. Am J Physiol1992; 263:C1040–C1048.
48.
KingBFWangSBurnstockG. P2 purinoceptor-activated inward currents in follicular oocytes of Xenopus laevis. J Physiol1996; 494:17–28.
49.
BoyerJLDelaneySMVillanuevaD. A molecularly identified P2Y receptor simultaneously activates phospholipase C and inhibits adenylyl cyclase and is nonselectively activated by all nucleoside triphosphates. Mol Pharmacol2000; 57:805–810.
50.
BogdanovYDDaleLKingBF. Early expression of a novel nucleotide receptor in the neural plate of Xenopus embryos. J Biol Chem1997; 272:12583–12590.
51.
SchwiebertEMZsemberyA. Extracellular ATP as a signaling molecule for epithelial cells. Biochim Biophys Acta2003;1615:7–32.
52.
RalevicVBurnstockG. Receptors for purines and pyrimidines. Pharmacol Rev1998; 50:413–492.
53.
BrazziniBGhersetichIHercogovaJ. The neuro–immuno–cutaneous–endocrine network: Relationship between mind and skin. Dermatol Ther2003; 16:123–131.
54.
PillaiSBikleDD. Adenosine triphosphate stimulates phosphoinositide metabolism, mobilizes intracellular calcium, and inhibits terminal differentiation of human epidermal keratinocytes. J Clin Invest1992;90:42–51.
55.
MizumotoNKumamotoTRobsonSC. CD39 is the dominant Langerhans cell-associated ecto-NTPDase: Modulatory roles in inflammation and immune responsiveness. Nat Med2002; 8:358–365.
56.
DzhandzhugazyanKNKirkinAFthor StratenP. Ecto-ATP diphosphohydrolase/CD39 is overexpressed in differentiated human melanomas. FEBS Lett1998; 430:227–230.
57.
ChanEYungWHBaumannKI. Cytoplasmic Ca2+ concentrations in intact Merkel cells of an isolated, functioning rat sinus hair preparation. Exp Brain Res1996; 108:357–366.
58.
EhrlichHPGriswoldTRRajaratnamJ. ATP-induced cell contraction with epidermolysis bullosa dystrophica recessive and normal dermal fibroblasts. J Invest Dermatol1986; 86:96–100.
59.
DamasJGarbackiNLiegeoisJF. [Control of cutaneous blood vessels.]Rev Med Liege2001; 56:846–849.
60.
SperlaghBDodaMBaranyiM. Ischemic-like condition releases norepinephrine and purines from different sources in supervised rat spleen strips. J Neuroimmunol2000; 111:45–54.
61.
CookSPMcCleskeyEW. Cell damage excites nociceptors through release of cytosolic ATP. Pain2002; 95:41–47.
62.
KoshlukovaSELloydTLAraujoMW. Salivary histatin 5 induces non-lytic release of ATP from Candida albicans leading to cell death. J Biol Chem1999; 274:18872–18879.
63.
GransteinRD. The skinny on CD39 in immunity and inflammation. Nat Med2002; 8:336–338.
64.
BoarderMRHouraniSM. The regulation of vascular function by P2 receptors: Multiple sites and multiple receptors. Trends Pharmacol Sci1998; 19:99–107.
65.
BeigiRKobatakeEAizawaM. Detection of local ATP release from activated platelets using cell surface-attached firefly luciferase. Am J Physiol1999; 276:C267–C278.
66.
ParkerJCSnowRL. Influence of external ATP on permeability and metabolism of dog red blood cells. Am J Physiol1972; 223:888–893.
67.
BergfeldGRForresterT. Release of ATP from human erythrocytes in response to a brief period of hypoxia and hypercapnia. Cardiovasc Res1992; 26:40–47.
68.
FilippiniATaffsRESitkovskyMV. Extracellular ATP in T-lymphocyte activation: Possible role in effector functions. Proc Natl Acad Sci USA1990; 87:8267–8271.
69.
SperlághBHaskóGNémethZ. ATP released by LPS increases nitric oxide production in raw 264.7 macrophage cell line via P2Z/P2X7 receptors. Neurochem Int1998; 33:209–215.
70.
JiangQMakDDevidasS. Cystic fibrosis transmembrane conductance regulator-associated ATP release is controlled by a chloride sensor. J Cell Biol1998; 143:645–657.
71.
LoomisWHNamikiSOstromRS. Hypertonic stress increases T cell IL-2 expression through a mechanism that involves ATP release, P2 receptor and p38 MAP kinase activation. J Biol Chem2003; 278:4590–4596.
72.
CotrinaMLLinJHAlves-RodriguesA. Connexins regulate calcium signaling by controlling ATP release. Proc Natl Acad Sci U S A1998; 95:15735–15740.
73.
RomanRMWangYLidofskySD. Hepatocellular ATP-binding cassette protein expression enhances ATP release and autocrine regulation of cell volume. J Biol Chem1997; 272:21970–21976.
CookPWAshtonNMPittelkowMR. Adenosine and adenine nucleotides inhibit the autonomous and epidermal growth factor-mediated proliferation of cultured human keratinocytes. J Invest Dermatol1995; 104:976–981.
83.
BrownJRCornellKCookPW. Adenosine- and adenine-nucle-otide-mediated inhibition of normal and transformed keratinocyte proliferation is dependent upon dipyridamole-sensitive adenosine transport. J Invest Dermatol2000; 115:849–859.
84.
OhanaGBar-YehudaSBarerF. Differential effect of adenosine on tumor and normal cell growth: Focus on the A, adenosine receptor. J Cell Physiol2001; 186:19–23.
85.
MerighiSMirandolaPMilaniD. Adenosine receptors as mediators of both cell proliferation and cell death of cultured human melanoma cells. J Invest Dermatol2002; 119:923–933.
86.
KennedyCTC. Mechanical and thermal injury. In: ChampionRHBurtonJLBurnsDA, eds. Textbook of Dermatology. Oxford: Blackwell Scientific, 1998; pp 883–895.
87.
KennedyWRWendelschafer-CrabbG. The innervation of human epidermis. Neurol Sci1993; 115:184–190.
88.
HilligesMWangLJohanssonO. Ultrastructural evidence for nerve fibers within all vital layers of the human epidermis. J Invest Dermatol1995; 104:134–137.
89.
ReznikM. [Structure and function of the cutaneous nervous system.]Pathol Biol (Paris)1996; 44:831–837.
90.
BesneIDescombesCBretonL. Effect of age and anatomical site on density of sensory innervation in human epidermis. Arch Dermatol2002; 138:1445–1450.
91.
TarkowskiENaverHWallinBG. Lateralization of cutaneous inflammatory responses in patients with unilateral paresis after poliomyelitis. J Neuroimmunol1996; 67:1–6.
92.
GibranNSJangYCIsikFF. Diminished neuropeptide levels contribute to the impaired cutaneous healing response associated with diabetes mellitus. J Surg Res2002; 108:122–128.
93.
HalataZGrimMBaumanKI. Friedrich Sigmund Merkel and his “Merkel cell”, morphology, development, and physiology: Review and new results. Anat Rec2003; 271A:225–239.
94.
HerbertMKHolzerP. [Neurogenic inflammation, I. Basic mechanisms, physiology and pharmacology.]Anasthesiol Intensivmed Notfallmed Schmerzther2002; 37:314–325.
95.
MorigiwaKFukudaYYamashitaM. [Neurotransmitter ATP and cytokine release.]Nippon Yakurigaku Zasshi2000; 115:185–192.
96.
Le PooleICYangFBrownTL. Altered gene expression in melanocytes exposed to 4-tertiary butyl phenol (4-TBP): Upregulation of the A2B adenosine receptor 1. J Invest Dermatol1999; 113:725–731.
97.
MerighiSVaraniKGessiS. Pharmacological and biochemical characterization of adenosine receptors in the human malignant melanoma A375 cell line. Br J Pharmacol2001; 134:1215–1226.
98.
EhrlichHPRajaratnamJBGriswoldTR. ATP-induced cell contraction in dermal fibroblasts: Effects of cAMP and myosin light-chain kinase. J Cell Physiol1986; 128:223–230.
99.
EhrlichHPRockwellWBCornwellTL. Demonstration of a direct role for myosin light chain kinase in flbroblast-populated collagen lattice contraction. J Cell Physiol1991; 146:1–7.
100.
SoliniAChiozziPMorelliA. Human primary fibroblasts in vitro express a purinergic P2X7 receptor coupled to ion fluxes, microvesicle formation and IL-6 release. J Cell Sci1999; 112:297–305.
101.
HuangNNWangDJHeppelLA. Stimulation of aged human lung fibroblasts by extracellular ATP via suppression of arachi-donate metabolism. J Biol Chem1993; 268:10789–10795.
102.
StenmarkKRGerasimovskayaENemenoffRA. Hypoxic activation of adventitial fibroblasts: Role in vascular remodeling. Chest2002; 122:326S–334S.
103.
WolffKWinkelmannRK. Ultrastructural localization of nucleoside triphosphatase in Langerhans cells. J Invest Dermatol1967; 48:50–54.
104.
GirolomoniGSantantonioMLPastoreS. Epidermal Langerhans cells are resistant to the permeabilizing effects of extracellular ATP: in vitro evidence supporting a protective role of membrane ATPase. J Invest Dermatol1993; 100:282–287.
105.
KimberICumberbatchMDearmanRJ. Cytokines and chemokines in the initiation and regulation of epidermal Langerhans cell mobilization. Br J Dermatol2000; 142:401–412.
106.
RandolphGJBeaulieuSPopeM. A physiologic function for p-glycoprotein (MDR-1) during the migration of dendritic cells from skin via afferent lymphatic vessels. Proc Natl Acad Sci U S A1998; 95:6924–6929.
107.
FerrariDChiozziPFalzoniS. Extracellular ATP triggers IL-1 beta release by activating the purinergic P2Z receptor of human macrophages. J Immunol1997; 159:1451–1458.
108.
BerchtoldSOgilvieALBogdanC. Human monocyte-derived dendritic cells express functional P2X and P2Y receptors as well as ecto-nucleotidases. FEBS Lett1999; 458:424–428.
109.
SakKBoeynaemsJMEverausH. Involvement of P2Y receptors in the differentiation of haematopoietic cells. J Leukoc Biol2003; 73:442–447.
110.
la SalaASebastianiSFerrariD. Dendritic cells exposed to extracellular adenosine triphosphate acquire the migratory properties of mature cells and show a reduced capacity to attract type 1 T lymphocytes. Blood2002; 99:1715–1722.
111.
SchnurrMThenFGalambosP. Extracellular ATP and TNF-alpha synergize in the activation and maturation of human dendritic cells. J Immunol2000; 165:4704–4709.
112.
MutiniCFalzoniSFerrariD. Mouse dendritic cells express the P2X7 purinergic receptor: Characterization and possible participation in antigen presentation. J Immunol1999; 163:1958–1965.
113.
NiHCapodiciJCannonG. Extracellular mRNA induces dendritic cell activation by stimulating tumor necrosis factor-alpha secretion and signaling through a nucleotide receptor. J Biol Chem2002; 277:12689–12696.
114.
IdzkoMDichmannSFerrariD. Nucleotides induce Chemotaxis and actin polymerization in immature but not mature human dendritic cells via activation of pertussis toxin-sensitive P2y receptors. Blood2002; 100:925–932.
115.
WilkinFStordeurPGoldmanM. Extracellular adenine nucleotides modulate cytokine production by human monocyte-derived dendritic cells: Dual effect on IL-12 and stimulation of IL-10. Eur J Immunol2002; 32:2409–2417.
116.
SluyterRWileyJS. Extracellular adenosine 5′-triphosphate induces a loss of CD23 from human dendritic cells via activation of P2X(7) receptors. Int Immunol2002; 14:1415–1421.
117.
FerrariDLa SalaAChiozziP. The P2 purinergic receptors of human dendritic cells: Identification and coupling to cytokine release. FASEB J2000; 14:2466–2476.
118.
la SalaAFerrariDDi VirgilioF. Alerting and tuning the immune response by extracellular nucleotides. J Leukoc Biol2003; 73:339–343.
119.
PantherECorintiSIdzkoM. Adenosine affects expression of membrane molecules, cytokine and chemokine release, and the T-cell stimulatory capacity of human dendritic cells. Blood2003; 101:3985–3990.
120.
PeirceSMSkalakTCRiegerJM. Selective A(2A) adenosine receptor activation reduces skin pressure ulcer formation and inflammation. Am J Physiol Heart Circ Physiol2001; 281:H67–H74.
121.
McPhersonJABarringhausKGBishopGG. Adenosine A(2A) receptor stimulation reduces inflammation and neointimal growth in a murine carotid ligation model. Arterioscler Thromb Vase Biol2001; 21:791–796.
122.
StreileinJWToewsGTGilliamJN. Tolerance or hypersensitivity to 2,4-dinitro-1-fluorobenzene: The role of Langerhans cell density within epidermis. J Invest Dermatol1980; 74:319–322.
123.
HosoiJMurphyGFEganCL. Regulation of Langerhans cell function by nerves containing calcitonin gene-related peptide. Nature1993; 363:159–163.
124.
TairaKNarisawaYNakafusaJ. Spatial relationship between Merkel cells and Langerhans cells in human hair follicles. J Dermatol Sci2002; 30:195–204.
