자외선에 의해 피부에서 유도되는 MMP-1과 proinflammatory cytokines의 발현 증가 과정에서의 serum amyloid A1의 역할

학위논문 (박사)-- 서울대학교 대학원 : 의과학과, 2017. 2. 정진호.Ultraviolet (UV) irradiation on the skin triggers photoaging-related phenotypes such as formation of wrinkles. UV ray up-regulates matrix metalloproteinase-1 (MMP-1), which in turn degrades extracellular matrix proteins, mostly collagens. Also, excessive UV irradiation on the skin causes cutaneous inflammation known as sunburn. Serum amyloid A1 (SAA1) is an acute-phase protein of which plasma concentration increases in response to inflammation. Although the expression of SAA1 in the skin was reported, its function in the skin is yet to be studied. In this research, I found that the expression of SAA1 was increased in acute UV-irradiated human buttock skin and photoaged human forearm skin in vivo as well as in acute UV-irradiated mouse dorsal skin in vivo. UV irradiation also increased SAA1 in normal human epidermal keratinocytes (NHEK) and treatment of recombinant human SAA1 (rhSAA1) induced MMP-1 and proinflammatory cytokines such as IL-6 and IL-8 in normal human dermal fibroblasts (NHDF)however, the effect of rhSAA1 on NHEK was limited compared to NHDF. Next, I demonstrated that NHDF treated with UV-irradiated keratinocyte conditioned media showed the increased MMP-1, IL-1β, IL-6, and IL-8 expressionhowever those increases in NHDF was inhibited by knockdown of SAA1 in NHEK. In addition, knockdown of Toll-like receptor 4 (TLR4) inhibited rhSAA1-induced MMP-1, IL-6, and IL-8 expression in NHDF. Taken together, my data showed that UV induced SAA1 production in NHEK, and this secreted SAA1 induced MMP-1, IL-6, and IL-8 expression in NHDF in a paracrine manner through TLR4 signaling pathway. Therefore, my results suggest that SAA1 can be a potential mediator for UV-induced MMP-1, IL-6, and IL-8 expression in human skin.Abstract ------------------------ p. i Contents ------------------------ p. iii List of tables ------------------------ p. v List of figures ------------------------ p. vi Introduction ------------------------ p. 1 Purposes ------------------------ p. 4 Chapter I. ------------------------ p. 5 Serum amyloid A1 secreted from UV-irradiated keratinocytes induces matrix metalloproteinase-1 in fibroblasts through Toll-like receptor 4. Materials and Methods ----------- p. 6 Results ----------- p. 18 Chapter II. ------------------------ p. 37 Serum amyloid A1 is induced by UV irradiation and detected by Toll-like receptor 4 to cause skin inflammation Materials and Methods ----------- p. 38 Results ----------- p. 47 Discussion ------------------------ p. 59 References ------------------------ p. 65 국문초록 ------------------------ p. 73Docto