Skip to main content
SpringerLink
Log in

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

  • Published:
Molecular Biology Reports Aims and scope Submit manuscript

Abstract

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Leung DY, Boguniewicz M, Howell MD et al (2004) New insights into atopic dermatitis. J Clin Investig 113:651–657

    PubMed  CAS  Google Scholar 

  2. Morar N, Willis-Owen SA, Moffatt MF, Cookson WO (2006) The genetics of atopic dermatitis. J Allergy Clin Immunol 118:24–34 quiz 35-36

    Article  PubMed  CAS  Google Scholar 

  3. Lubbe J (2003) Secondary infections in patients with atopic dermatitis. Am J Clin Dermatol 4:641–654

    Article  PubMed  Google Scholar 

  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 186:2372–2381

    Article  PubMed  CAS  Google Scholar 

  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 284:8174–8184

    Article  PubMed  CAS  Google Scholar 

  6. Mosser DM, Edwards JP (2008) Exploring the full spectrum of macrophage activation. Nat Rev Immunol 8:958–969

    Article  PubMed  CAS  Google Scholar 

  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 4:139–147

    Article  PubMed  Google Scholar 

  8. Taylor PR, Martine z-Pomares L, Stacey M, Lin HH, Brown GD, Gordon S (2005) Macrophage receptors and immune recognition. Annu Rev Immunol 23:901–944

    Article  PubMed  CAS  Google Scholar 

  9. Yingkui Y, Victor J, Victor JHruby, Chen Min (2009) Novel binding motif of ACTH analogues at the melanocortin receptors. Biochemistry 48(41):9775–9784

    Article  Google Scholar 

  10. Kathleen G, Mountjoy L, Robbins S (1992) The cloning of a family of genes that encode the melanocotin receptor. J Sci 257:1248–1251

    Article  Google Scholar 

  11. Schaffer JV, Bolognia JL (2001) The melanocortin-1 receptor: red hair and beyond. J Arch Dermatol 137:1447–1485

    Google Scholar 

  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 27:388–394

    Google Scholar 

  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 443:340–344

    Article  PubMed  Google Scholar 

  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 2:374–383

    Article  PubMed  Google Scholar 

  15. Steingrimsson E, Copeland NG, Jenkins NA (2004) Melanocytes and the microphthalmia transcription factor network. Annu Rev Genet 38:365–411

    Article  PubMed  CAS  Google Scholar 

  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 56:641–646

    Article  PubMed  CAS  Google Scholar 

  17. Jialing Y, Zhixue L (2008) High-Throughput Screening of crude antagonists of MC1R. J shang hai university (natural science) 14:216–220

    Google Scholar 

  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 73:1786–1795

    Article  PubMed  CAS  Google Scholar 

  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 152:182–191

    Article  PubMed  CAS  Google Scholar 

  20. Mirzapoiazova T, Kolosova IA, Moreno L et al (2007) Suppression of endotoxin-induced inflammation by taxol. Eur Respir J 30:429–435

    Article  PubMed  CAS  Google Scholar 

  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 4:139–147

    Article  PubMed  Google Scholar 

  22. Korhonen R, Lahti A, Kankaanranta H, Moilanen E (2005) Nitric oxide production and signaling in inflammation. Curr Drug Targets Inflamm Allergy 4:471–479

    Article  PubMed  CAS  Google Scholar 

  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 J

    Article  PubMed  CAS  Google Scholar 

  24. Joshua SY, Ann R, Feng C et al (2006) Statical amalysis of realtime PCR data. J BMC Bioinformatics 7(85):1471–2105

    Google Scholar 

  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 12:241–248

    Article  PubMed  CAS  Google Scholar 

  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 28:700–703

    PubMed  CAS  Google Scholar 

  27. Hodge DR, Hurt EM, Farrar WL (2005) The role of IL-6 and STAT3 in inflammation and cancer. Eur J Cancer 41:2502–2512

    Article  PubMed  CAS  Google Scholar 

  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 101:782–785

    PubMed  CAS  Google Scholar 

  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 17:463–467

    Article  PubMed  Google Scholar 

  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 7:895–899

    Article  PubMed  CAS  Google Scholar 

  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 150:1177–1185

    PubMed  CAS  Google Scholar 

  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 18:393–410

    Google Scholar 

  33. Mountjoy KG, Robbins LS, Mortrud MT, Cone RD (1992) The cloning of a family of genes that encode the melanocortin receptors. Science 257:1248–1251

    Article  PubMed  CAS  Google Scholar 

  34. April CS, Barsh GS (2007) Distinct pigmentary and melanocortin 1 receptor-dependent components of cutaneous defense against ultraviolet radiation. Plos Genet 3(1):e9

    Article  PubMed  Google Scholar 

  35. Steingrimsson E, Copeland NG, Jenkins NA (2004) Melanocytes and the microphthalmia transcription factor network. Annu Rev Genet 38:365–411

    Article  PubMed  CAS  Google Scholar 

  36. Cone RD (2005) Anatomy and regulation of the central melanocortin system. Nat Neurosci 8:571–578

    Article  PubMed  CAS  Google Scholar 

  37. Chhajlani V (1996) Distribution of cDNA for melanocortin receptor subtypes in human tissues. Biochem Mol Biol Int 38:73–80

    PubMed  CAS  Google Scholar 

  38. Ni XP, Butler AA, Cone RD, Humphreys MH (2006) Central receptors mediating the cardiovascular actions of melanocyte stimulating hormones. J Hypertens 24:2239–2246

    Article  PubMed  CAS  Google Scholar 

  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 51:287–317

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

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).

Author information

Authors and Affiliations

  1. College of Animal Science and Veterinary Medicine, Jilin University, 130062, Changchun, China

    Wei Chen, Hai’e Qu, Zhou Song, Zhanqing Yang, Qinghua Huang, Meixia Huo, Bo Liu & Qiaoling Zhang

  2. College of Animal Science and Technology, Jilin Agricultural University, 130118, Changchun, China

    Jianping Li & Huaizhi Jiang

  3. Faculty of Animal Science and Technology, Yunnan Agricultural University, 650201, Kunming, China

    Jinlong Huo

Authors
  1. Wei Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jianping Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hai’e Qu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Zhou Song
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Zhanqing Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jinlong Huo
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Huaizhi Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Qinghua Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Meixia Huo
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Bo Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Qiaoling Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Qiaoling Zhang.

Additional information

Wei Chen and Jianping Li contributed equally to this study.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Chen, W., Li, J., Qu, H. et al. The melanocortin 1 receptor (MC1R) inhibits the inflammatory response in Raw 264.7 cells and atopic dermatitis (AD) mouse model. Mol Biol Rep 40, 1987–1996 (2013). https://doi.org/10.1007/s11033-012-2256-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11033-012-2256-x

Keywords

Search

Navigation