| [Background] Psoriasis(psoriasis)is a common,relapsing and refractory chronic inflammatory proliferative disease,which is a complex pathological process related to many factors,such as inheritance,immunity,infection and so on.According to its clinical manifestations,it can be divided into four types including psoriasis vulgaris,pustular psoriasis,psoriatic arthritis and erythroderma psoriasis.The recurrence of this disease is high,seriously affects the quality of patients’ life.The pathogenesis is not clear,it is still one of the key researched diseases in dermatology.It is widely concerned that the pathogenesis of psoriasis is caused by immune dysfunction in individuals with genetic susceptibility to external environment,abnormal proliferation and differentiation of keratinocytes,and increased dermal angiogenesis.Activated keratinocytes can produce inflammatory cytokines and chemokines which lead to the aggregation and activation of immune cells and then results in chronic inflammatory reaction.Micro RNASS(mi RNAs)are small RNAs with a length of about 22-25 nucleotides,located in the non-coding region of the genome and responsible for post-transcriptional regulation by complementing the 3’untranslated region(3’untranslated region)of the target gene’s m RNA.Therefore,the degradation or translation of the target gene m RNA was inhibited.In recent years,it has been found that micro RNA plays an important role in the pathogenesis of some chronic inflammatory diseases and tumors,participates in the regulation of immune response,and is closely related to the expression of related inflammatory factors and angiogenesis factors.However,the pathogenesis of psoriasis is accompanied with inflammation and dermal papilla angiogenesis,indicates that micro RNA is closely related to the pathogenesis of psoriasis.There are more than 250 micro RNA has been shown abnormal expression in peripheral blood or skin lesions of psoriatic patients.Mcro RNA-146(mi R-146)is one of the abnormal expressed mi RNAs in peripheral blood of psoriatic patients.Most vertebrates have two genes encoding mi R-146,mi R-146 a and mi R-146 b.The human mi R-146 a is the most studied member of mi R-146 family.In recent years,many researchs have found that mi R-146 a plays an important role in regulating immunity,inflammation,angiogenesis,etc.The relationship between mi R-146 a and the pathogenesis of psoriasis is not completely clear.The previous study of mi R-146 a and immune-mediated inflammation in psoriasis was conducted,and now mainly studied the the relationship between mi R-146 a and dermis angiogenesis in psoriasis.By using biological prediction software,we found that mi R-146 a has many target genes,including TRAF6,IRAK1,IRAK2,FARAK2,EGF-Rn and Smad4,etc.Mi R-146 a is involved the occurrence and development of various diseases in physiological activities by interacting with target genes.The gene binding of mi R-146 a to one of Smad4(Smads protein family can inhibit the expression of Smad4 in post-transcriptional level.Smad4 is an essential transduction molecule in TGF-β / Smads signaling pathway.TGF-β can inhibit the proliferation of keratinocytes,maintain the stability in the epidermal environment.The decrease expression of Smad4 may affect the signal transduction pathway of TGF-β / Smads,block the inhibition of TGF-β signal on the excessive proliferation of keratinocytes,increasing the number of keratinocytes.Stimulated by inflammatory factors such as IL-17,the proliferative keratinocytes secreted VEGF and other related angiogenic factors,which increased the capillaries of dermal papilla,increased permeability and aggravated the inflammatory reaction of dermis.[Objective] In our previous study,we found that the expression of mi R-146 a was increased in peripheral blood mononuclear cells and lesions in psoriasis vulgaris patients.Smad4 was the transduction molecule of TGF-β / Smads signal transduction pathway.It is also an important target gene of mi R-146 a.Therefore,we speculate that mi R-146 a may bind to Smad4 in the pathogenesis of psoriasis and directly participate in the excessive proliferation of keratinocytes in psoriasis,and may also regulate the expression of Smad4 downstream related factors such as VEGF.Thus participates in the inflammatory reaction of psoriasis and promote angiogenesis process,promote the occurrence and development of psoriasis.[Methods] 1.Twenty patients with psoriasis vulgaris were randomly selected.The skin of the patients with plaque lesions was taken and the normal skin was used as the control group.The results were semi-quantitatively analyzed by Image Pro-Pluss-IPP image processing system after immunohistochemical technique,and the average of gray value was measured to reflect the expression intensity of the specimen.2.Double luciferase assay was used to detect the the activity of luciferase after co-transfected of plasmids containing Smad4 and mi R-146 a mimics binding fragments in human embryonic renal cells.3.Cultured human immortalized epidermal cell line,mi R-146 a mimics and inhibitor were transfected respectively.The expression levels of Smad4 and VEGF in each group were detected by RT-PCR method.4.After the Ha Cat cells were cultured to a certain number,Smad4 interference fragment si RNA(small-interference RNAs)and blank fragments were transfected respectively.The expression levels of Smad4 and VEGF proteins were detected by Western Blot method after a certain concentration of IL-17.[Results] 1.The expression of Smad4 in psoriatic lesions was lower than that of normal control groups(P < 0.05),but the expression of VEGF was higher than control groups(P < 0.05).There was a negative correlation between the expression of Smad4 and the PASI score of the patients.While VEGF expression shows the positive correlation with PASI score of the patients(r1=-0.719,P<0.01,r2= 0.794,P<0.01)2.The heterotopic expression of mi R-146 a and luciferase activity in the report system containing wild type Smad4 3’-UTR decreased significantly.Smad4 was an effective binding target for mi R-146 a.(P<0.05)3.Ha Cat cells were cultured and overexpressed mi R-146 a showing effectively inhibition of target gene Smad4 and promote the expression of VEGF,but the inhibition of mi R-146 a expression did not change significantly to the target gene Smad4.4.Ha Cat cells were transfected with si RNAs(knockout Smad4 gene)and detected by Western Blot method.The expression of Smad4 protein was significantly lower than that of negative control group,while the VEGF expression was higher than control group.[Conclusions] 1.The expression of Smad4 in psoriasis vulgaris patients decreased and had a negative correlation with the PASI score of the patients.The increase of VEGF expression was positively correlated with the PASI score of the patients.It suggested that Smad4 and VEGF co-promote the occurrence and development of psoriasis.The expression level of them can be used as one of the criteria for judging the severity of psoriasis vulgaris.2.Smad4 is one of the target genes of mi R-146 a,and it can bind to mi R-146 a specifically.3.mi R-146 a can inhibit the expression of target gene Smad4 at the transcriptional level.Meanwhile,it can promote the expression of VEGF.4.mi R-146 a may regulate the expression of VEGF by the target gene Smad4 and the decrease of Smad4 can effectively promote the expression of VEGF,suggesting that Smad4 plays a negative role in angiogenesis of psoriasis. |
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