Ciclosporin A inhibits production of interleukin-12/23p40 and interleukin-23 by the human monocyte cell line, THP-1.

Ciclosporin (Cs)A is an effective treatment for psoriasis. However, to date, the effect of CsA on the production of interleukins (ILs) is unknown. We investigated how CsA affects production of IL-12/23p40 and IL-23 production by the human monocyte cell line, THP-1, which is able to differentiate into macrophage-like cells or normal human keratinocytes (NHKs). THP-1 cells were preincubated with CsA, then stimulated with lipopolysaccharide (LPS), polyinosinic:polycytidylic acid or adenosine triphosphate. The levels of IL-12/23p40 and IL-23 released into the supernatant were assayed by ELISA. CsA significantly reduced both IL-12/23p40 and IL-23 production by LPS-stimulated THP-1 cells, but not in LPS-stimulated macrophage-like differentiated THP-1 cells. None of the stimuli used significantly induced either IL-12/23p40 or IL-23 production in NHKs. CsA inhibits not only IL-12/23p40 and IL-12p70, but also heterodimeric IL-23 production by human monocytes, which may be one possible mechanism for the therapeutic efficacy of CsA in psoriasis.

Serum lipocalin-2 levels are increased in patients with psoriasis.

The protein lipocalin (LCN)-2 is known to be related to insulin resistance, obesity and atherosclerotic diseases. Psoriasis is an inflammatory skin disease related to metabolic syndrome. The aim of this study was to examine the relationship between serum LCN2 levels and indicators for metabolic syndrome and inflammatory cytokine levels in patients with psoriasis. Serum LCN2 levels were measured in patients with psoriasis, atopic dermatitis (AD) or bullous pemphigoid (BP), and compared with those of healthy controls. Serum LCN2 levels were also compared with several indicators for metabolic syndrome, and with serum levels of interleukin (IL)-6 and tumour necrosis factor (TNF)-α, two markers of inflammation. Serum LCN2 levels in patients with psoriasis were significantly higher than those of healthy controls, but there was no significant correlation between serum LCN2 and body mass index. Serum LCN2 levels also correlated with serum IL-6 and TNF-α levels in patients with psoriasis. Serum LCN2 levels are a general indicator for increased inflammation in the patients with psoriasis.

Suppression by apigenin of peritoneal metastasis of intestinal adenocarcinomas induced by azoxymethane in Wistar rats.

The effect of a naturally occurring flavonoid apigenin on the development of bombesin-enhanced peritoneal metastasis from intestinal adenocarcinomas induced by azoxymethane was investigated in male Wistar rats. From the start of the experiment, rats were given weekly s.c. injections of azoxymethane (7.4 mg/kg body weight) for 10 weeks and s.c. injection of bombesin (40 microg/kg body weight) every other day, and from week 16, s.c. injections of apigenin (0.75 or 1.5 mg/kg body weight) every other day until the end of the experiment in week 45. Bombesin significantly increased the incidence of intestinal tumors and cancer metastasis to the peritoneum in week 45. It also significantly increased the labeling index of intestinal cancers. Although administration of apigenin at either dose with bombesin had little or no effect on the enhancement of intestinal carcinogenesis by bombesin, the location, histologic type, depth of involvement, infiltrating growth patterns and labeling index, it was found to decrease significantly the incidence of cancer metastasis. Apigenin significantly decreased the incidence of lymphatic vessel invasion of adenocarcinomas, which was enhanced by bombesin. In vitro experiments revealed that apigenin inhibited bombesin-enhanced phosphorylation of mitogen-activated protein kinase (MAPK), but not matrix metalloprotease (MMP)-9 expression. Our findings indicate that apigenin inhibits cancer metastasis through inhibition of phosphorylation of MAPK.

Visfatin enhances CXCL8, CXCL10, and CCL20 production in human keratinocytes.

Psoriasis patients are frequently associated with metabolic syndromes. Such associations are possibly mediated by adipokines. We investigated the in vitro effects of visfatin (an adipokine) on chemokine expression in human keratinocytes. Normal human keratinocytes were incubated with visfatin, and their chemokine production was analyzed by ELISA and RT-PCR. Visfatin enhanced TNF-α-induced CXC chemokine ligand (CXCL) 8, CXCL10, and CC chemokine ligand (CCL) 20 secretion and mRNA expression in keratinocytes, although visfatin alone was ineffective. A small interfering RNA against nuclear factor-κB (NF-κB) p65 suppressed the visfatin-induced production of CXCL8, CXCL10, and CCL20 whereas a small interfering RNA against signal transducer and activator of transcription (STAT) 3 suppressed CXCL8 induction. This indicates the involvement of NF-κB in CXCL8, CXCL10, and CCL20 induction by visfatin and the involvement of STAT3 in CXCL8 induction. Visfatin alone increased the transcriptional activity and tyrosine phosphorylation of STAT3, which was suppressed by Janus kinase (JAK) 2 inhibitor. Visfatin enhanced basal and TNF-α-induced NF-κB activity and inhibitory κB (IκB) α phosphorylation, which was suppressed by IκB kinase inhibitor. Visfatin induced the tyrosine and serine phosphorylation of JAK2 and IκB kinase α/ß, respectively. Intraperitoneal injection of visfatin elevated mRNA and protein levels of CXCL1, CXCL10, and CCL20 in murine skin. These results suggest that visfatin enhances CXCL8, CXCL10, and CCL20 production in human keratinocytes and homologous chemokine production in murine skin. Visfatin may induce the infiltration of type 1 or type 17 helper T cells or neutrophils to the skin via chemokine induction and thus link metabolic syndromes to psoriasis.