High-dose infusion of IgG (IVIG) is used to treat autoimmune and inflammatory diseases, including Kawasaki disease (KD). Although the immunomodulatory effects of IVIG on blood cells such as macrophages have been well studied, its effects on tissue cells remain unclear. Here, we show that high-dose IgG specifically and completely inhibited TNF-α-induced, but not IL-1β-induced, secretion of proinflammatory cytokines such as G-CSF and IL-6 by cultured human coronary artery endothelial cells (HCAECs). Highdose IgG did not inhibit TNF-α-mediated early signaling events of the NF-κB and MAPK pathways but it potently inhibited gene expression of G-CSF and IL-6 12 h after TNF-α-stimulation. Interestingly, suppression of the G-CSF and IL-6 gene expression correlated closely with functional inhibition of a transcription factor, C/EBPδ, whose binding sites in the promoters of G-CSF and IL-6 have been shown to be critical for their transcriptional activation. Furthermore, the inhibitory effect of intact IgG on HCAECs was exerted mainly via its F(ab') 2 fragment, and not its Fc fragment. These findings suggest that the clinical effects of IVIG on KD patients are at least in part due to its direct anti-inflammatory effects on the coronary endothelium, which is a major lesion site in the pathogenesis of KD. Keywords:Coronary artery endothelial cells r IVIG r Kawasaki disease r TNF-α Supporting Information available online IntroductionIntravenous infusion of IgG was originally used as a replacement therapy for patients with hypogammaglobulinemia in the Correspondence: Dr. Akio Matsuda e-mail: amatsuda@nch.go.jp early 1950s. High-dose infusion of IgG (IVIG) is now used to treat autoimmune and inflammatory diseases such as idiopathic thrombocytopenic purpura, Guillain-Barre syndrome, and Kawasaki disease (KD). To date, a number of possible mechanisms for the immunomodulatory and anti-inflammatory effects of IVIG therapy have been described [1,2] KD is an acute systemic vasculitis seen in infants and young children [9,10], and it is frequently associated with coronary artery aneurysms [11]. IVIG is a well-established standard therapy for KD that effectively reduces systemic inflammation and the incidence of coronary artery lesions (CALs) [12][13][14]. The clinical evidence strongly suggests that IVIG exerts its beneficial effects by attenuating coronary artery inflammation. However, the mechanisms underlying these clinical effects of IVIG on coronary endothelium are not well understood, and some patients do not respond to IVIG and develop CALs. Thus, we examined the in vitro effects of high-dose IgG on cultured human coronary artery endothelial cells (HCAECs), which is a major lesion site in the pathogenesis of KD.We used TNF-α as an inflammatory stimulus in most of our in vitro experiments for the following reasons. First, during the acute phase of KD, serum levels of TNF-α are significantly elevated and correlate with the incidence of CALs in acute KD patients [15,16]. Second, TNF-α was shown to be necessary for induction of coro...

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Adriamycin linked to oxidized dextran (ADM-OXD) via Schiff's base formation was compared with free adriamycin with regard to antitumor activity, acute toxicity and plasma pharmacokinetics in rats following i.v. administration. ADM-OXD showed higher activity against Walker carcinosarcoma 256 than free adriamycin. On the other hand, the acute toxicity of ADM-OXD was about three times less than that of free adriamycin. In contrast to free adriamycin, a very high plasma level of adriamycin was found after i.v. administration of ADM-OXD. The area under the plasma concentration curve with ADM-OXD was about 160-fold higher than with free adriamycin. Thus, the improvement of the therapeutic index in the case of ADM-OXD might be due to the difference in the disposition of ADM-OXD and free adriamycin in rats.

Tissue distribution of the radioactivities after intravenous administration of [14C]adriamycin ([14C]ADM) or [14C]ADM linked to oxidized dextran ([14C]ADM-OXD) in mouse bearing Lewis lung carcinoma (LLC) and rat bearing Walker 256 carcinosarcoma was studied. ADM conjugated with OXD increased plasma half-life and gave high area under the plasma concentration-time curve (AUC). The AUC values were 13.0 and 5.8 times higher than those of the [14C]ADM group in mice and rats, respectively. In the tumor tissues, AUC values of the [14C]ADM-OXD group were also respectively 1.6 and 1.9 times higher than those of the [14C]ADM group. However, the AUC values in the heart of the [14C]ADM-OXD group were about half those of [14C]ADM group in both animals. Thus the distribution of ADM was changed by the conjugation with OXD. The excretion profile of ADM was also changed by the conjugation. During 6 h after administration, [14C]ADM-OXD was mainly excreted into rat urine at 45.2% of the original dose, but in the [14C]ADM group recovery in urinary excretion was 4.2%. Using [14C]ADM-OXD and ADM-[14C]OXD, the respective tissue distribution of ADM and OXD portions in the ADM-OXD was studied in rats bearing Walker 256. The radioactivities of both [14C]ADM-OXD and ADM-[14C]OXD groups increased in tumor and liver within 1 h after administration. In the liver, both radioactivities were retained for 24 h, which suggested that ADM and OXD were retained as conjugated form, however, different behavior was observed between the two groups in tumor tissues.(ABSTRACT TRUNCATED AT 250 WORDS)

VolatileC6-aldehydes such as hexanal, m-3-hexenal and Jrarcs-2-hexenal, along with the corresponding alcohols, characterize flavors of plant tissues and are found in a variety of plants.1} Lipoxygenase and hydroperoxide lyase (HPO lyase) are responsible for the enzymatic formation of these C6-aldehydes from linoleic and linolenic acids originating from lipids.2) In a previous paper we reported that cultured green cells of alfalfa had the ability to produce the C6-aldehydes from linoleic and linolenic acids.3) The present paper describes further characterization of the C6-aldehyde-forming enzyme system of the cultured alfalfa cells.