The Multiple Roles of Urocanic Acid in Health and Disease

Trans-urocanic acid (trans-UCA) is synthesized in the skin, liver, and brain. It a major natural moisturizing factor skin maintains its pH. In it isomerizes to cis-UCA following exposure UVR. Both isomers fulfill multiple roles health disease. Cis-UCA has immunomodulatory properties linked with several cutaneous diseases such as cancer, atopic dermatitis, urticaria associates systemic including sclerosis. The levels of UCA brain, urine, feces reflect some physiological processes may be disease biomarkers. have therapeutic potential for range disorders. Urocanic (UCA) was first discovered more than hundred years ago urine dog, hence, name (Jaffe, 1874Jaffe M. Concerning new constituent dogs [in German].Berichte der Deutschen Chemischen Gesellschaff. 1874; 7: 1669-1673Crossref Scopus (14) Google Scholar). located mainly uppermost layers human particularly stratum corneum, where constitutes approximately 0.7% dry weight epidermis (Tabachnick, 1957Tabachnick J. acid, acid-soluble, ultraviolet-absorbing compound guinea pig epidermis.Arch Biochem Biophys. 1957; 70: 295-298Crossref PubMed (37) pH found which essential optimal function enzymes antimicrobial defenses, due (Krien Kermici, 2000Krien P.M. Kermici Evidenced existence self-regulated enzymatic process within corneum -an unexpected role urocanic acid.J Invest Dermatol. 2000; 115: 414-420Abstract Full Text PDF (123) Scholar) together other factors, free fatty acids sodium-hydrogen exchanger-1 activation (Proksch, 2018Proksch E. Lowering pH: improved barrier function, anti-ageing beyond.Br J 2018; 179: 254-255Crossref (1) concentration varies considerably between individuals, from around 4 nM per cm2 34 cm2, an individual, there little difference at sun-exposed unexposed body sites (Kavanagh et al., 1995Kavanagh G. Crosby Norval skin: analysis site variation.Br 1995; 133: 728-731Crossref (38) amount does not correlate age, sex, pigmentation, photosensitivity, minimal erythema dose, thickness (de Fine Olivarius 1998ade F. Wulf H.C. photosensitivity healthy children.Br 1998; 139: 605-609Crossref (9) Proteins rich histidine, predominantly FLG, contains 10% histidine residues, break down into smaller peptides amino keratinocytes (KCs) become terminally differentiated. Histidase (L-histidine ammonia lyase) activated this subsequent formation histidine. accumulates enzyme that catalyzes it, urocanase, present skin. also liver recently brain (Zhu 2018Zhu H. Wang N. Yao L. Chen Q. Zhang R. Qian al.Moderate UV enhances learning memory by promoting novel glutamate biosynthetic pathway brain.Cell. 173: 1716-1727Abstract (61) where, contrast urocanase catabolizes imidazolone-propinic further breakdown glutamic (GLU). absorbs UVR and, doing so, naturally occurring trans form until equilibrium reached on continued maximum 60% cis-UCA. Following irradiation, serum (Moodycliffe 1993Moodycliffe A.M. Kimber I. Simpson T.J. Characterization monoclonal antibody cis-urocanic acid: detection irradiated mice immunoassay.Immunology. 1993; 79: 667-672PubMed excreted up 12 days (Kammeyer 1997Kammeyer A. Pavel S. Asghar S.S. Bos J.D. Teunissen M.B. Prolonged increase after single total-body ultraviolet exposure.Photochem Photobiol. 1997; 65: 593-598Crossref (53) action spectrum production most effective UVB waveband 280–310 nm (McCloone 2005McCloone P. Simics Barton Gibbs N.K. An vivo.J 2005; 124: 1071-1074Abstract (52) Because relative abundance ability absorb UVR, initially proposed act sunscreen protect against sunburn damage DNA (reviewed Morrison, 1985Morrison Photochemistry photobiology acid.Photodermatol. 1985; 2: 158-165PubMed This confirmed subsequently (Barresi 2011Barresi C. Stremnitzer Mlitz V. Kezic Kammeyer Ghannadan al.Increased sensitivity histidinemic radiation suggests crucial endogenous photoprotection.J 2011; 131: 188-194Abstract (88) Scholar; Bruhs 2016Bruhs Eckhart Tschachler Schwarz T. regulator Langerhans cells.J 2016; 136: 1735-1737Abstract (4) Scholar), although sun protection estimated only 1.5 1996de sunscreening effect acid.Photodermatol Photoimmunol Photomed. 1996; 12: 95-99Crossref (35) Furthermore, vitro singlet oxygen generation excitation trans-UCA mimics vivo photoaging showing plays through UVA sensitization (Hanson Simon, 1998Hanson K.M. 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However, shown Table 1, receptors been found, leading possibility vary cell type. addition, because position GLU metabolic pathway, aspects are becoming apparent.Table 1Direct Responses Multiple Cell TypesCell TypeResponseReceptor (If Investigated)Mechanism Investigated)ReferenceKCs (from foreskin cultured vitro)Inability induce PGE2 but synergized histamine increased production—Increased KCs response histamineHart 1997Hart P.H. Jaksic Swift el-Ghorr A.A. Finlay-Jones J.J. Histamine involvement UVB- acid-induced contact hypersensitivity responses.Immunology. 601-608Crossref (73) 1995Jaksic Watson C.J. Spencer L.K. Santucci Hart Cis-urocanic synergizes keratinocytes: link indomethacin-inhibitable UVB-induced immunosuppression.Photochem 61: 303-309Crossref (80) ScholarKCs (primary human, immortalized buttock vitro)Stimulation synthesis apoptotic deathNot determined detected independently serotonin or PAF inhibitorsIntracellular ROS modulate EGFR signalingKaneko 2011Kaneko K. Walker S.L. Lai-Cheong Maatsui M.S. Young A.R. cis-Urocanic prostaglandin E2 release death via reactive species keratinocytes.J 1262-1271Abstract (19) Scholar, Kaneko 2009Kaneko Travers J.B. Matsui stimulates primary platelet-activating receptors.J 2009; 129: 2567-2573Abstract (13) 2008Kaneko Smetana-Just Natsui John al.cis-Urocanic initiates gene transcription Immunol. 181: 217-224Crossref (40) Scholar)KCs (human vitro)Increased expression encoding ?-galactoside-binding lectin, galectin-7, highly expressed patients actinic keratosis—Galectin-7 can upregulate apoptosis inhibit IL-2 IFN-? mRNA Jurkat T cellsYamaguchi 2013Yamaguchi Hiromasa Kabashima-Kubo Yoshiola Nakamura Galectin-7, induced B down-modulates cytokine lymphocytes.Exp 2013; 22: 832-849Crossref (25) (murine)After topical application mouse before exposure, no significant binding (1.2 × 10?3– 2.1 10?3 ng [14C] mg assessed)—UCA photobinding immunosuppressionIJland 1998IJland S.A. Cervak Steenvoorden D.P. Bouscarel Hug D. al.Urocanic photobind immunosuppressive doses UVB.Photochem 67: 222-226Crossref ScholarMurine KC line (PAM212)Induction ROS5-HTR—Sreevidya 2010Sreevidya C.S. Fukunaga Khaskhely N.M. Masaki Ono Nishigori al.Agents reverse photocarcinogenesis affect repair.J 2010; 130: 1428-1437Abstract (70) ScholarDermal fibroblasts vitro)Inhibition cAMP PGE1 confluent cultures.No isolated hamster hepatocytes HT29 cells stimulated glucagon vasoactive intestinal peptideNot 5HT2A receptorNot stimulation phosphodiesterase breakdownBouscarel 1998Bouscarel Gettys T.W. Phillips T.M. DeFabo Regulation cyclic AMP acid.Photochem 324-331Crossref ScholarLCs (human, enriched 8–25% purified 70–90%)No regulation antigen presentation mixed epidermal cell-lymphocyte reaction——Rattis 1995Rattis F.M. Péguet-Navarro Courtellemont Schmitt failed allostimulatory function.Photochem 914-916Crossref (12) (murine)Reduced tumor vivo; reduced transgenic vitro—Reduction reversed antagonists nor indomethacin. Reduction IL-12Beissert 2001Beissert Ruhlemann Mohammad Grabbe El-Ghorr al.IL-12 prevents inhibitory effects cells: implications photocarcinogenesis.J 2001; 167: 6232-6238Crossref (66) Beissert 1997Beissert Mohammed Torri Lonati Yan Z. Morrison al.Regulation 159: 92-96PubMed Scholar)Skin DCs (mouse)Significant reduction number ATPase + skinHistamine-1 histamine-2, histamine-3 skin—Gilmour 1992Gilmour J.W. Neuvonen Pasanen histamine-like immunosuppression delayed 1992; 9: 250-254PubMed Moodycliffe 1992Moodycliffe dendritic migration.Immunology. 77: 394-399PubMed 1990Norval cis-isomer 1990; 243-248PubMed ScholarT lymphocytes vitro)Significant IL-10 decrease neuroantigen-specific cells, CD4+CD25+FoxP3+ regulatory T-cell percentages5HT2A receptorIncreased phosphorylated forms ERK1/2 JNK2Correale Farez, 2013Correale Farez M.F. Modulation sclerosis sunlight exposure: Neuroimmunol. 261: 134-140Abstract (28) ScholarCD4+ (murine spleen cells)Elevated anti-CD3 CD4+ cells—cis-UCA targets directly splenic non-T macrophagesHolán 1998Holán Kuffová Zajícová Krulová Filipec Holler 161: 3237-3241PubMed ScholarMonocytes (purified blood elutriation vitro)cis-UCA, serotonin, 5-HT2A agonist suppressed TNF-? production, indomethacin demonstrated different use membrane receptorsNot identified type 1 5HT2A, 5HT3, 5HT4, 5HT7 receptorscis-UCA, PGE2-dependent mechanismHart 1993Hart Jones C.A. K.L. al.Cis-urocanic peripheral monocyte suppresses indirectly necrosis factor-alpha levels.J 150: 4514-4523PubMed Woodward 2006Woodward E.A. Prele C.M. remains elusive.J 2006; 126: 1191-1193Abstract ScholarMonocyte-derived antigen-presenting capacity autoreactive priming assayNot known (no mRNA)—Correale ScholarBone marrow–derived (murine)Significant inhibition LPS-induced CXCL1, secretion——Albert 2010Albert Thiesen Churchill Madsen attenuates acute dextran sodium sulphate-induced inflammation.PLoS One. 5e13676Crossref ScholarPeripheral sensory nerves (rats vivo)Dose-dependent microvascular flow blister base rat hind footpad. Small direct result largely dependent neuropeptides—Release substance P calcitonin gene-related peptide, activate MCs important cis-UCA–induced suppression, well LCsHart 1999Hart Grimbaldeston M.A. G.J. Hosszu E.K. A critical dermal mast responses mice.Photochem 1999; 807-812Crossref (43) Khalil 2001Khalil Townley neuropeptide nerves.J 117: 886-891Abstract ScholarCancer vitro)Dose-dependent viability melanoma, bladder carcinoma cervical carcinoma, fibrosarcoma weakly acidic extracellular pH—Induction necrotic death, annexin-V caspase-3 intracellular 0.5 units. Metabolic activity impaired arrest cycleArentsen 2012Arentsen Jansen C.F. Hulsbergen-van de Kaa Laihia J.K. Pylkkänen Leino al.Antitumor experimental urothelial bladder.J Urol. 2012; 187: 1445-1449Crossref 2010Laihia Kallio J.P. Taimen Kuiari Kähärri V.M. Protodynamic acidification promotes melanoma 2431-2439Abstract 2009Laihia Pylkkanen Laato Bostrom P.J. therapy cancer: results treatment concept.BJU Int. 104: 1233-1238Crossref (11) Peuhu 2010Peuhu Kaunisto Eriksson J.E. Molecular protodynamic cells.BMC Cancer. 10: 521Crossref (6) ScholarCorneal epithelial conjunctival vitro)Complete IL-8, IL-6 secretion, decreased activity, viability——Jauhonen 2017Jauhonen H.M. Oksala O. Viiri Sironen Alajuuma al.Topical ocular surface irritation both IgE-independent -mediated model.Graefes Arch Clin Ophthalmol. 2017; 255: 2357-2362Crossref 2009Viiri Jauhonen Kauppinen Ryhänen Paimela Hyttinen UV-B-induced interleukin-6 -8 secretion cytotoxicity corneal vitro.Mol Vis. 15: 1799-1805PubMed ScholarAbbreviations: 5HT, 5-hydroxytryptamine; 5-HTR, 5-hydroxytryptamine and/or receptor; ATPase, adenosine triphosphatase; DC, cell; ERK, signal–regulated kinase; JNK, c-Jun N-terminal KC, keratinocyte; LC, LPS, lipopolysaccharide; MC, PAF, platelet activating factor; PGE, E; UCA, acid.The same did respond equivalent concentrations trans-UCA. Where known, mechanism detailed. Reports varied often contradictory. Further reported without identification responding Open table tab Abbreviations: acid. review, date linking cis-UCA, synthetically produced, molecules outlined. cases, se determinants processes; quantity biomarker pathways. investigated agents. All these briefly considered. Since mid-1980s, traditional view induces immunosuppression, likely contribute diminution controlling tumorigenesis. oxidative genes associated apoptosis, growth arrest, stress (Table 1) (Kaneko Sreevidya antigens inhibited incidence tumors chronically UVB-irradiated were treated throughout exposures cis-UCA–specific mAb compared unirradiated (Beissert Finally, limited humans higher level biopsies squamous periphery (Decara 2008Decara J.M. Aguilera Abdala Sánchez Figueroa F.L. Herrera Screening basal skin.Exp 17: 806-812Crossref percentage previous carcinomas malignant melanomas controls, patient groups dose 1998bde Lock-Andersen Larsen F.G. melanoma.Br 138: 986-992Crossref additional property relates cancer rather cancer. microenvironment acidified, boosts invasiveness metastasis, whereas stromal neutral. acidify cytosol transporting protons intracellularly (termed photodynamic concept), leads signaling cascade (Laihia xenografts immunodeficient intratumoral injections three times weekly 2 weeks. By similar process, (Peuhu orthotopic model, administered intravesically occasions muscle invasive 100% 43% instilled acid-treated (Arentsen summary, reducing immunity. Its lead local selected cancers. reduce subacute inflammation 2012Laihia Kujari Topical oedema mouse.Br 506-513Crossref models, mild pH, applied topically hydrocortisone tacrolimus decreasing irritation, edema, erythema. infiltration neutrophils neutrophils. chronic spontaneous (transient wheals angioedema), cis-UCA-to-trans-UCA ratio controls (Pham 2017Pham D.L. Lim Joo Park H.S. Leung D.Y.M. Ye Y.M. Increased cis-to-trans urticarial patients.Sci Rep. 1318Crossref (8) Scho