Nitric oxide may directly induce the psoriatic disease process via suppression of keratinocyte apoptosis and induction of keratinocyte hyperproliferation

Abstract

Nitric oxide (NO) has been supposed to induce the psoriatic disease process indirectlythrough increase of release and also effects of substance P and calcitonin gene-relatedpeptide. This paper discusses the potential direct roles of NO by induction of keratinocytehyperproliferation and suppression of keratinocyte apoptosis.NO has been shown to exert a biphasic effect on keratinocytes based on its concentration:increasing proliferation and decreasing differentiation of keratinocytes at low concentrationsbut producing the reverse effects at high concentrations (≥500μm). Therefore, NO, having amaximum concentration of about 0.01μm in the psoriatic lesions, more likely induceskeratinocyte hyperproliferation rather than suppressing it.Low production of NO in psoriasis occurs in the face of high overexpression of induciblenitric oxide synthase (iNOS) mRNA and protein and may be due to a) overexpression ofarginase 1, which regulates iNOS activity by competing for the common substrate L-arginine,b) overexpression of calcitonin gene-related peptide, which inhibits iNOS activity, c) NO’sregulatory effect on its own production by binding to heme which mediates iNOSdimerization, and d) NO’s inhibition of the release of nerve growth factor which in synergywith TNF-α induces iNOS. Noteworthy, neopterin and cutaneous polyamines, which are alsooverexpressed in the psoriatic lesions, contribute further to the low production of NO viasuppression of the expression of iNOS gene. Based on the observations that psoriatickeratinocytes are resistant to the induction of apoptosis and that NO, at low concentrations, iscapable of suppressing apoptosis, this author suggests the apoptosis -suppressant effect of NOas another potential role for NO in inducing the psoriatic disease process.