Molecular Biology Reports

, Volume 40, Issue 2, pp 1987–1996 | Cite as

The melanocortin 1 receptor (MC1R) inhibits the inflammatory response in Raw 264.7 cells and atopic dermatitis (AD) mouse model

  • Wei Chen
  • Jianping Li
  • Hai’e Qu
  • Zhou Song
  • Zhanqing Yang
  • Jinlong Huo
  • Huaizhi Jiang
  • Qinghua Huang
  • Meixia Huo
  • Bo Liu
  • Qiaoling ZhangEmail author


The alpha melanocyte stimulating hormone receptor (MC1R) is one of five G-protein coupled receptors belonging to the melanocortin subfamily, MC1R gene has been known to play a major role in regulating of fur color in mammals, and α-MSH and ACTH are endogenous nonselective agonists for MC1R. However, we found that MC1R was highly expressed in Raw 264.7 cells which were important inflammatory cells involved in the initiation of inflammatory responses. In addition, Cyclic AMP is not only a key molecule in the MC1R signal transduction pathway, but dampen innate immune-mediated responses. These intriguing biological results triggered the further conformation studies; it suggested that MC1R was very likely to be an important role in immunoregulation. In this study, we were to investigate the immunosuppressive effects of MC1R on inflammation in lipopolysaccharide (LPS) stimulated Raw 264.7 cells and LPS induced vivo 2-chloro-1,3,5-trinitrobenzene (TNCB)-induced atopic dermatitis (AD) model. The effects of the MC1R antagonist psoralen on pro-inflammatory cytokines and signaling pathways were analyzed by enzyme-linked immunosorbent assay, western blot, real-time fluorescence quantitative PCR and Histological analysis. Our results show a consistent and marked effect of high concentrations of MC1R antagonist psoralen increased the level of MC1R mRNA in Raw 264.7 cells by cumulative feedback regulation through preferential binding of MC1R. Moreover, as evidenced by inhibiting the LPS-induced TNF-α, IL-6 and enhancing the expression level of cyclic AMP protein in vitro. In vivo study it was also observed that psoralen promoted on histopathologic changes in the skin tissue of TNCB-induced AD mice. Taken together, our results suggest that MC1R decrease the inflammation in vitro and vivo, and might be a therapeutic signaling pathway to against inflammatory diseases.


MC1R Cytokines Inflammation action Psoralen Atopic dermatitis 



This work was supported by grants from the National Natural Science Foundation of China (NSFC) (Nos. 30800807 and 31072097) and the Special Foundation for Postdoctor of China Ministry of Education (No. 20100471261).


  1. 1.
    Leung DY, Boguniewicz M, Howell MD et al (2004) New insights into atopic dermatitis. J Clin Investig 113:651–657PubMedGoogle Scholar
  2. 2.
    Morar N, Willis-Owen SA, Moffatt MF, Cookson WO (2006) The genetics of atopic dermatitis. J Allergy Clin Immunol 118:24–34 quiz 35-36PubMedCrossRefGoogle Scholar
  3. 3.
    Lubbe J (2003) Secondary infections in patients with atopic dermatitis. Am J Clin Dermatol 4:641–654PubMedCrossRefGoogle Scholar
  4. 4.
    Nelson MP, Christmann BS, Werner JL (2011) IL-33 and M2a alveolar macrophages promote lung defense against the atypical fungal pathogen Pneumocystis murina. J Immunol 186:2372–2381PubMedCrossRefGoogle Scholar
  5. 5.
    Liao CP, Lasbury SH, Durant Y et al (2009) Pneumocystis mediates over expression of anti zyme inhibitor resulting in increased polyamine levels and apoptosis in alveolar macrophages. J Biol Chem 284:8174–8184PubMedCrossRefGoogle Scholar
  6. 6.
    Mosser DM, Edwards JP (2008) Exploring the full spectrum of macrophage activation. Nat Rev Immunol 8:958–969PubMedCrossRefGoogle Scholar
  7. 7.
    Satoh H, Firestein GS, Billings PB, Harris JP, Keithley EM (2003) Proinflammatory cytokine expression in the endolymphatic sac during inner ear inflammation. J Assoc Res Otolaryngol 4:139–147PubMedCrossRefGoogle Scholar
  8. 8.
    Taylor PR, Martine z-Pomares L, Stacey M, Lin HH, Brown GD, Gordon S (2005) Macrophage receptors and immune recognition. Annu Rev Immunol 23:901–944PubMedCrossRefGoogle Scholar
  9. 9.
    Yingkui Y, Victor J, Victor JHruby, Chen Min (2009) Novel binding motif of ACTH analogues at the melanocortin receptors. Biochemistry 48(41):9775–9784CrossRefGoogle Scholar
  10. 10.
    Kathleen G, Mountjoy L, Robbins S (1992) The cloning of a family of genes that encode the melanocotin receptor. J Sci 257:1248–1251CrossRefGoogle Scholar
  11. 11.
    Schaffer JV, Bolognia JL (2001) The melanocortin-1 receptor: red hair and beyond. J Arch Dermatol 137:1447–1485Google Scholar
  12. 12.
    Liesel M, Fitz G, Jayne LF et al (2006) Effect of melantan, [Nle4.D-Phe7]-a-MSH. on melanin synthesis in humans with MC1R variant alleles. J Pept 27:388–394Google Scholar
  13. 13.
    D’Orazio JA, Nobuhisa T, Cui R et al (2006) Topical drug rescue strategy and skin protection based on the role of Mc1r in UV-inducedanning. Nature 443:340–344PubMedCrossRefGoogle Scholar
  14. 14.
    Schaffler A, Scholmerich J, Buechler C (2006) The role of ‘adipotropins’ and the clinical importance of a potential hypothalamic–pituitary–adipose axis. Nat Clin Pract Endocrinol Metab 2:374–383PubMedCrossRefGoogle Scholar
  15. 15.
    Steingrimsson E, Copeland NG, Jenkins NA (2004) Melanocytes and the microphthalmia transcription factor network. Annu Rev Genet 38:365–411PubMedCrossRefGoogle Scholar
  16. 16.
    Wessells H, Gralnek D, Dorr R, Hruby VJ, Hadley ME, Levine N (2000) Effect of an alpha-melanocyte stimulating hormone analog on penile erection and sexual desire in men with organic erectile dysfunction. Urology 56:641–646PubMedCrossRefGoogle Scholar
  17. 17.
    Jialing Y, Zhixue L (2008) High-Throughput Screening of crude antagonists of MC1R. J shang hai university (natural science) 14:216–220Google Scholar
  18. 18.
    Ho YS, Lai CS, Liu HI, Ho SY, Tai C, Pan MH et al (2007) Dihydrolipoic acid inhibits skin tumor promotion through anti-inflammation and anti-oxidation. Biochem Pharmacol 73:1786–1795PubMedCrossRefGoogle Scholar
  19. 19.
    Tumurkhuu G, Koide N, Dagvadorj J et al (2008) The mechanism of development of acute lung injury in lethal endotoxic shock using alpha-galactosylceramide sensitization. Clin Exp Immunol 152:182–191PubMedCrossRefGoogle Scholar
  20. 20.
    Mirzapoiazova T, Kolosova IA, Moreno L et al (2007) Suppression of endotoxin-induced inflammation by taxol. Eur Respir J 30:429–435PubMedCrossRefGoogle Scholar
  21. 21.
    Satoh H, Firestein GS, Billings PB, Harris JP, Keithley EM (2003) Proinflammatory cytokine expression in the endolymphatic sac during inner ear inflammation. J Assoc Res Otolaryngol 4:139–147PubMedCrossRefGoogle Scholar
  22. 22.
    Korhonen R, Lahti A, Kankaanranta H, Moilanen E (2005) Nitric oxide production and signaling in inflammation. Curr Drug Targets Inflamm Allergy 4:471–479PubMedCrossRefGoogle Scholar
  23. 23.
    Libby P (2000) Coronary artery injury and the biology of atherosclerosis: inflammation, thrombosis, and stabilization. Am J Cardiol 86:3J–8J discussion 8 J-9 JPubMedCrossRefGoogle Scholar
  24. 24.
    Joshua SY, Ann R, Feng C et al (2006) Statical amalysis of realtime PCR data. J BMC Bioinformatics 7(85):1471–2105Google Scholar
  25. 25.
    Huo Meixia, Chen Na, Chi Gefu et al (2012) Traditional medicine alpinetin inhibits the inflammatory response in Raw 264.7 cells and mouse models. Int Immunopharmacol 12:241–248PubMedCrossRefGoogle Scholar
  26. 26.
    Giebelen IA, van Westerloo DJ, LaRosa GJ, de Vos AF, van der Poll T (2007) Local stimulation of alpha 7 cholinergic receptors inhibits LPS-induced TNF-alpha release in the mouse lung. Shock 28:700–703PubMedGoogle Scholar
  27. 27.
    Hodge DR, Hurt EM, Farrar WL (2005) The role of IL-6 and STAT3 in inflammation and cancer. Eur J Cancer 41:2502–2512PubMedCrossRefGoogle Scholar
  28. 28.
    Leser HG, Gross V, Scheibenbogen C, Heinisch A, Salm R, Lausen M et al (1991) Elevation of serum interleukin-6 concentration precedes acute-phase response and reflects severity in acute pancreatitis. Gastroenterology 101:782–785PubMedGoogle Scholar
  29. 29.
    Remick DG, Bolgos GR, Siddiqui J, Shin J, Nemzek JA (2002) Six at six: interleukin-6 measured 6 h after the initiation of sepsis predicts mortality over 3 days. Shock 17:463–467PubMedCrossRefGoogle Scholar
  30. 30.
    Marklund L, Moller MJ, Sandberg L, Andersson L (1996) A missense mutation in the gene for melanocyte-stimulating hormone receptor (MC1R) is associated with the chesnut coat color in horses. Mamm Genome 7:895–899PubMedCrossRefGoogle Scholar
  31. 31.
    Kijas JMH, Wales R, Tornsten A, Chardon P, Moller M, Andersson L (1998) Melanocortin receptor 1 (MC1R) mutations and coat color in pigs. Genetics 150:1177–1185PubMedGoogle Scholar
  32. 32.
    Garcı′a-Borro′ n JC, Sa′ nchez-Laorden BL, Jime′ nez-Cervantes C (2005) Melanocortin-1 receptor structure and functional regulation. Pigment Cell Res 18:393–410Google Scholar
  33. 33.
    Mountjoy KG, Robbins LS, Mortrud MT, Cone RD (1992) The cloning of a family of genes that encode the melanocortin receptors. Science 257:1248–1251PubMedCrossRefGoogle Scholar
  34. 34.
    April CS, Barsh GS (2007) Distinct pigmentary and melanocortin 1 receptor-dependent components of cutaneous defense against ultraviolet radiation. Plos Genet 3(1):e9PubMedCrossRefGoogle Scholar
  35. 35.
    Steingrimsson E, Copeland NG, Jenkins NA (2004) Melanocytes and the microphthalmia transcription factor network. Annu Rev Genet 38:365–411PubMedCrossRefGoogle Scholar
  36. 36.
    Cone RD (2005) Anatomy and regulation of the central melanocortin system. Nat Neurosci 8:571–578PubMedCrossRefGoogle Scholar
  37. 37.
    Chhajlani V (1996) Distribution of cDNA for melanocortin receptor subtypes in human tissues. Biochem Mol Biol Int 38:73–80PubMedGoogle Scholar
  38. 38.
    Ni XP, Butler AA, Cone RD, Humphreys MH (2006) Central receptors mediating the cardiovascular actions of melanocyte stimulating hormones. J Hypertens 24:2239–2246PubMedCrossRefGoogle Scholar
  39. 39.
    Cone RD, Lu D, Koppula S et al (1996) The melanocortin receptors: agonists, antagonists, and the hormonal control of pigmentation. Recent Prog Horm Res 51:287–317PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2012

Authors and Affiliations

  • Wei Chen
    • 1
  • Jianping Li
    • 2
  • Hai’e Qu
    • 1
  • Zhou Song
    • 1
  • Zhanqing Yang
    • 1
  • Jinlong Huo
    • 3
  • Huaizhi Jiang
    • 2
  • Qinghua Huang
    • 1
  • Meixia Huo
    • 1
  • Bo Liu
    • 1
  • Qiaoling Zhang
    • 1
    Email author
  1. 1.College of Animal Science and Veterinary MedicineJilin UniversityChangchunChina
  2. 2.College of Animal Science and TechnologyJilin Agricultural UniversityChangchunChina
  3. 3.Faculty of Animal Science and TechnologyYunnan Agricultural UniversityKunmingChina

Personalised recommendations