The differential expression of IL-18 mRNA in the psoriatic lesions between SP psoriasis (typical Asian psoriasis) and LP psoriasis (typical Western psoriasis) has previously been reported9
. Since then, we have analyzed and found that a similar difference in the IL-18 mRNA expression was also observed between SP and LP psoriasis patients who have the same Asian ethnic background (data not shown).
When we analyzed the caspase-1 mRNA expression level between LP and SP psoriasis to indirectly determine the difference in the activity of IL-18, we could observe that the caspase-1 mRNA expression was significantly increased in the lesional skin compared with non-lesional skin and the normal skin in only SP psoriasis patients, suggesting that the increased expression of caspase-1 mRNA in the SP lesional skin may be more related to the activation of IL-18 (). In case of the level of the STAT-6 mRNA expression between LP and SP psoriasis, the expression levels were not different between them. There was only a significant elevation of the STAT-6 mRNA level in the SP lesional skin compared with the level in the normal skin (), and this implicated that the function of Th2 cytokines may be more prominent in the SP lesional skin compared with that of normal skin, which is presumably due to the response to inflammation since STAT-6 is known to be increased by the activation of Th2 cytokines like IL-4 or IL-10.
Cytokines have long been known to induce MMPs10-13,18-21
. However MMPs can also influence certain cytokine activities22
. Therefore, the counter regulation of MMPs and cytokines seems to be important for both activities. Several MMPs were previously reported to be elevated in psoriatic lesions ()23-26
. The IFN-α produced by plasmacytoid predendritic cells was recently demonstrated to be an important initiator in the development of psoriasis27,28
. An MMP-1 expression has been reported to be induced by IFN-α29
which has been shown to be involved in the early development of psoriasis in a ARG-/- xenograft model27
. Thus, the expression level of MMP-1 mRNA is predicted to have some role in the early development of psoriasis. In our study, the MMP-1 mRNA expression level in the LP non-lesional skin was not significantly different from the MMP-1 mRNA expression level in the SP non-lesional skin, although the MMP-1 mRNA expression levels in both LP lesional skin and SP lesional skin were elevated compared to the MMP-1 mRNA expression level in normal skin. Therefore, the elevation of the MMP-1 mRNA expression in the lesional skin is thought to be the secondary response to the inflammatory cytokines that are produced in psoriasis lesions. However, Flisiak et al30,31
reported that the elevated levels of MMP-1 and TIMP-1 in psoriatic plasma and the levels of MMP-1 and TIMP-1 in psoriatic plasma were inversely correlated to the disease severity (a decrease in MMP-1 and an increase in TIMP-1). The level of MMP-1 in psoriatic scales was also shown to be inversely correlated to the psoriasis severity30
. Although MMP-2 was shown to be overexpressed in the psoriatic lesions23,32
, we could only observe the significant elevation of the MMP-2 mRNA level in the lesions of SP psoriasis (and not in LP psoriasis), as compared with the MMP-2 mRNA level in the non-lesional skin. This elevation is thought to be due to a secondary inflammatory response. MMP-9 can be induced by cytokines such as TNF-α and IFN-γ, which are known to be upregulated in psoriasis33-38
. The MMP-9 mRNA expression level in the LP non-lesional skin was elevated compared with that in the SP non-lesional skin, indicating that there is a difference in the MMP-9 mRNA expression between the two clinical types of psoriasis. This tendency of the MMP-9 suggests that the elevation of the MMP-9 mRNA expression in the non-lesional skin of psoriasis vulgaris is related to the large size type of lesion. However, there was no significant difference in the expression of TIMP-1, which is a specific inhibitor of MMP-9, between the non-lesions of the two types of psoriasis. Although several MMPs are known to be elevated in psoriasis, these elevations have also been reported to be associated with other skin disorders25,39,40
. In lichen planus, the digestion of the basement membrane by MMP-2 may contribute to the pathogenesis by inducing an altered integrin expression in basal keratinocytes and ultimately blister formation39
. MMP-11 (stromelysin-3) seems to be associated with benign fibroblastic tumors25
. Increased expressions of MMP-2, MMP-9 and MMP-13 were demonstrated in the lesional skin of patients suffering with bullous pemphigoid40
. However, these changes in the MMPs seem to be due to a secondary phenomenon of inflammation or tumorigenesis. A recent study on anti-TNF-α therapy in psoriasis patients suggested that the clinical improvement correlated more with the level of MMP-9 than with the level of MMP-2 in the lesions41,42
. Therefore, the increased expression of MMP-9 in the non-lesional skin of LP psoriasis patients is thought to be more relevant to the pathogenesis of psoriasis than with the expression of other MMPs. An increased expression of MMP-9 during the progression of carcinogenesis, and decreased tumor metastasis in MMP-9-deficient mice have been reported43,44
. These findings suggested that MMP-9 is a crucial factor for the progression of carcinogenesis and metastasis. Therefore, further study is necessary to elucidate whether MMP-9 is a factor that governs the expansion of the lesions in psoriasis patients.
Changes in matrix metalloproteinases and tissue inhibitors of metalloproteinases in psoriatic lesions
In summary, among the mRNA expression levels of caspase-1, STAT-6, MMP-1, MMP-2, MMP-9 and TIMP-1 mRNA, the expressions of caspase-1, MMP-1, MMP-2 and MMP-9 mRNA were increased in the SP lesional skin compared with that of the SP non-lesional skin (the STAT-6 mRNA in the SP lesional skin was increased compared with that of normal skin). The level of the MMP-9 expression from the LP non-lesional skin was significantly increased compared with the MMP-9 level in the SP non-lesional skin, suggesting that the increased level of the MMP-9 mRNA expression in the non-lesional skin of psoriasis vulgaris patients is related to the large size type of lesion. Further study is necessary to discover the meaning of the differential expression of these genes in patients suffering with SP and LP psoriasis.