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CURRENT HYPOTHESIS
Year : 2006  |  Volume : 51  |  Issue : 3  |  Page : 194-195
Possible molecular mechanisms involved in the down-regulation of expression and activity of inducible nitric oxide synthase in the psoriatic lesions


Dermatology Department, Autoimmune Diseases Research Center, Shiraz University of Medical Sciences, Shiraz, Iran

Correspondence Address:
M R Namazi
P. O. Box 71955-687, Shiraz
Iran
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0019-5154.27984

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How to cite this article:
Namazi M R. Possible molecular mechanisms involved in the down-regulation of expression and activity of inducible nitric oxide synthase in the psoriatic lesions. Indian J Dermatol 2006;51:194-5

How to cite this URL:
Namazi M R. Possible molecular mechanisms involved in the down-regulation of expression and activity of inducible nitric oxide synthase in the psoriatic lesions. Indian J Dermatol [serial online] 2006 [cited 2020 Nov 23];51:194-5. Available from: https://www.e-ijd.org/text.asp?2006/51/3/194/27984


Psoriatic lesions are characterized by severe over expression of Th1 cytokines which are known to induce the production of high, inducible, concentrations of NO[1] However, NO levels are only slightly elevated above psoriatic plaques as compared to uninvolved skin[1] and it is estimated that in psoriatic lesions, NO concentrations are about 0.00005 mM near the skin surface and increase to a maximum of about 0.01 mM in the middle of the rete pegs.[2] These concentrations lie within the constitutive, not inducible, range of NO production. The fact that lower NO concentrations are detected does not necessarily mean that the source of the production is through one of the pathways, however it suggests that the inducible isoform may not be active in the psoriatic epidermis, especially in the superficial areas.

This fact could resolve the reservation raised by some workers that NO may exert an inhibitory effect on the Th1 immune response underlying psoriasis,[3] as NO at low concentrations, in contrast to high concentrations, encourages the development of Th1 cells.[4] Moreover, it is supposed that NO, at this low concentrations, may induce keratinocyte hyperproliferation and dedifferentiation seen in psoriasis.[1]

How could low, constitutive, concentrations of NO in the face of severe overproduction of Th1 cytokines be explained?

Bruch-Gerharz et al[4] have recently shown that arginase 1, which regulates iNOS activity by competing for the shared substrate L-arginine, is also overexpressed in the psoriatic lesions, being co-expressed with iNOS.

Furthermore, calcitonin gene-related peptide (CGRP), which is overexpressed in the psoriatic lesions,[5] is capable of inhibition of iNOS activity and therefore decreasing NO concentration.[6] Given that NO is known to increase the release of CGRP,[5] NO is supposed to control its own production indirectly by effecting the overexpression of CGRP. The dimerization of iNOS, mediated by the binding of iron protoporphyrin IX (heme) to the oxygenase domain of iNOS, is essential for its activation. Since NO binding to heme renders it insoluble, the iron released from the oxygenase domain prevents dimerization of iNOS proteins and uncouples already formed iNOS dimers. NO may thus directly regulate its own production.[6] The above-mentioned three mechanisms act to limit the activity of iNOS and thus can explain the presence of constitutive concentrations of NO in the face of expression of iNOS - mRNA and protein. Two other mechanisms, discussed below, could be supposed to be operative in hampering the full expression of iNOS in the psoriatic plaques. If theses mechanisms were not operative, higher expression of iNOS could have lead to more NO levels despite the inhibitory effects of arginase 1 and CGRP:

Neopterin, a compound belonging to the unconjugated pteridines group, is mainly synthesized by monocytes/macrophages upon stimulation with Th1-deriven IFN-gamma and has been proposed to inhibit the NO-induced apoptotic cell death via suppression of cytokine-induced NO synthesis, say, via suppressing the iNOS gene expression.[7] It has been demonstrated that serum and urinary neopterin levels are elevated in psoriatics.[8] Thus, neopterin may also be partly responsible for the low NO concentration in the psoriatic lesions. Moreover, cutaneous polyamines, which are known to be increased in psoriasis,[9] further decrease the concentration of NO through suppression of iNOS gene expression.[10]

Conclusively, several mechanisms could be considered to be operative in hampering the rise of NO levels in psoriatic plaques and in keeping it within the constitutive range; hence, it is unlikely that a therapeutic approach targeting only one mechanism could lead to a significant improvement of this clinical conundrum.

 
   References Top

1.Bruch-Gerharz D, Schnorr O, Suschek C, Beck KF, Pfeilschifter J, Ruzicka T, et al . Arginase 1 over-expression in psoriasis: Limitation of inducible nitric oxide synthase activity as a molecular mechanism for keratinocyte hyperproliferation . Am J Pathol 2003;162:203-11.  Back to cited text no. 1      
2.Sarill NJ, Weller R, Sherratt JA. Mathematical modeling of nitric oxide regulation of rete peg formation in psoriasis. J Theor Biol 2002;214:1-16.   Back to cited text no. 2      
3.Mckenzie RC, Weller R. Langerhans cells, keratinocytes, nitric oxide and psoriasis. Immunol Today 1998;19:427-8.  Back to cited text no. 3  [PUBMED]  [FULLTEXT]  
4.Niedbala W, Wei XQ, Piedrafita D, Xu D, Liew FY. Effects of nitric oxide on the induction and differentiation of Th1 cells. Eur J Immunol 1999;29:2498-505.  Back to cited text no. 4  [PUBMED]  [FULLTEXT]  
5.Namazi MR. A complementary note on the Morhenn's hypothesis on the pathomechanism of psoriasis. Immunol Lett 2003;85:223.  Back to cited text no. 5  [PUBMED]  [FULLTEXT]  
6.Taylor AW, Yee DE, Streilein JW. Suppression of nitric oxide generated by inflammatory macrophages by calcitonin-gene related peptide in aqueous humor. Invest Ophthalmol Vis Sci 1998;39:1372-8.  Back to cited text no. 6      
7.Reider J, Amann A, Schlosser M. Suppressive effects of neopterin on inducible nitric oxide synthase gene expression in ovarian carcinoma cells in vitro. Pteridines 2001;12:1-8.  Back to cited text no. 7      
8.Sanchez-Regana M, Catasus M, Creus L, Umbert P. Serum neopterin as an objective marker of psoriatic disease activity. Acta Derm Venereol 2000;80:185-7.  Back to cited text no. 8      
9.Lowe NJ, Breeding J, Russel D. Cutaneous polyaminas in psoriasis. Br J Dermatol 1982;107:21-5.  Back to cited text no. 9      
10.Baydoun AR, Morgan DM. Inhibition of ornithine decarboxylase potentiates nitric oxide production in LPS-activated J774 cells. Br J Pharmacol 1998;125:1511-6.  Back to cited text no. 10      




 

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