Anti‐inflammatory effects of high‐dose IgG on TNF‐α‐activated human coronary artery endothelial cells

Abstract

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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“…The apparently exclusive IL‐1β dependence of HCAEC activation by TLR‐4–stimulated human monocytes is remarkable, as other studies have demonstrated that HCAECs were responsive to recombinant TNF with overlapping profiles of induced gene expression in response to IL‐1β . However, an enhanced sensitivity of HCAECs toward IL‐1β, in terms of IL‐6 release, has already been suggested .…”

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“…IVIG products have been demonstrated to be effective in the treatment of inflammatory disorders [16]. To date, a number of possible mechanisms for the immunomodulatory and antiinflammatory effects of IVIG therapy have been described [17,18], including anticomplement effects [19], anti-idiotypic neutralization of pathogenic autoantibodies [20], immune regulation via an inhibitory Fc receptor [16,21], enhancement of regulatory T cells [22] and inhibition of Th17 differentiation [23]. Thus, IVIG may mediate a wide variety of biological and immunomodulatory effects via various types of blood cells [23].…”