According to their structures and substrate specificity MMPs

According to their structures and substrate specificity, MMPs are divided into five major groups: collagenases (e.g., MMP1), gelatinases (e.g., MMP2, MMP9), stromelysins (e.g., MMP3, MMP10), matrilysins (e.g., MMP7), and membrane-type MMPs [7]. Among them, MMP1 is a major collagenase that degrades the most abundant ECM components in the dermis, namely, type I and III collagen. In contrast, MMP2 degrades type I and IV collagen. MMP3 mediates the activation of other MMPs including MMP1 and pro-MMPs, as well as the degradation of type I collagen. MMP10 activates pro-MMPs and MMP7 degrades elastin [7]. The efficacy of MMP inhibition varies with each TIMP [3]. TIMP1 is a strong inhibitor of many MMPs [8]. TIMP1 and −3 inhibit the function of latent or pro-MMP9, and TIMP2 and −3 interact with pro-MMP2 [8]. There are no satisfactory therapies for fibrotic and sclerotic disorders. Given that long-term chronic exposure to ultraviolet (UV) rays leads to a decrease of dermal collagen [9], phototherapy with UVA or UVB has been undertaken for scleroderma with a beneficial outcome [10]. UVA1 radiation increases the expression of MMP1 and −3 in the skin, and decreases type I and III collagen in the skin of a bleomycin-induced mouse model of scleroderma [11]. Similarly, UVB exposure increases the expression of MMPs including MMP1 and MMP3 in human skin [6] and human dermal fibroblasts in vitro[5], but the precise mechanisms behind this are not fully understood. Aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that is constitutively expressed in a variety of 17-DMAG sale [12], [13]. Activated AHR translocates from the cytoplasm into the nucleus, which leads to the transcription of target genes such as CYP1A1 and CYP1B1 in human keratinocytes and fibroblasts, respectively [13], [14], [15], [16]. AHR signaling is an integral part of UV responses because UV exposure upregulates CYP1A1 and CYP1B1 expression and their upregulation is canceled by AHR deficiency or a selective AHR antagonist [17], [18]. The L-tryptophan metabolite 6-formylindolo[3,2-b]carbazole (FICZ) is a photo-product formed by UV exposure in humans [19]. Notably, FICZ exhibits high affinity for AHR [19], [20], indicating that FICZ might be one of the effective chromophores that mediate the biological responses induced by UV. In accordance with this notion, FICZ mediates various biological responses including cell differentiation [21] and immune modulation [22] as well as UVA-induced oxidative stress [23]. We and other groups have shown that FICZ inhibits the TGF-ß-induced collagen production in fibroblasts [13], [24], [25]. In this study, we present evidence that FICZ is a potent MMP1 inducer via microtubule-associated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) activation of the mitogen-activated protein kinase (MAPK) signaling cascade. Notably, the function of FICZ was shown to be AHR-dependent.
Material and methods
Results
Discussion UV responses activate multiple intracellular signal pathways including the MAPK cascade [27]. Although UV radiation induces deleterious cell damage by generating DNA photo-products in the nucleus, reactive oxygen species, and metabolizing enzymes such as CYP1A1 and CYP1B1 [29], [30], its anti-fibrotic effects are clinically applicable to fibrosing or sclerotic diseases such as scleroderma [10]. It is known that UV inhibits collagen synthesis and promotes its degradation by enhancing the expression of MMPs [5], [6], [11]. A variety of chromophores and photosensitizers have been reported to be produced in the skin in response to UV radiation [31]. FICZ is a tryptophan photo-product, which binds to AHR with high affinity [19], [20], [30]. Notably, FICZ mediates, at least in part, similar biological effects as UV exposure [19], [20], [30], indicating that FICZ might be one of the effectors of UV responses. In accordance with this, we previously demonstrated that FICZ inhibits TGF-β-mediated collagen production in NHDFs [13]. In this study, we showed (1) that UVB radiation upregulated MMP1 and MMP3 expression; (2) that FICZ upregulated MMP1, but not MMP3, expression; (3) that UVB-mediated MMP1 upregulation was dependent on the MEK/ERK, p38 MAPK, and JNK pathways, while FICZ-induced MMP1 upregulation was dependent on only MEK/ERK signaling; and (4) that FICZ-mediated MMP1 upregulation was canceled in AHR-knockdown NHDFs. In addition, FICZ did not alter the expression of TIMPs.