In addition, they have been shown to chemoattract CD4 T cells and immature dendritic cells through CCR6, suggesting that they link innate and adaptive immunity 10. hBD3 and 4 also chemoattract monocytes and Mϕ 8, 11, and hBD3 has been shown to activate monocytes and myeloid dendritic cells through TLR-1/2 by inducing expression of co-stimulatory molecules and NF-κB 12. Recently,
human α-defensins present in neutrophil granules have been shown to display anti-inflammatory properties 13. In this paper we show that hBD3 does not induce TNF-α or IL-6 in Mϕ and in fact has potent anti-inflammatory effects Selleck Acalabrutinib on both human and mouse primary Mϕ. The anti-inflammatory effect was also evident in vivo and in the THP-1 human monocytic cell line and RAW264.7 mouse Mϕ cell line. hBD3 effectively inhibited the inflammatory GDC-0973 purchase effects of both LPS and CD40 ligand (CD40L). Recently it has been shown that hBD3 can interact with melanocortin receptors in vitro 14 and a dominant mutation
in this gene in dogs and arctic wolves is causative for black coat colour 15. Despite melanocortin 1 receptor (MC1R) and melanocortin 3 receptor (MC3R) being expressed on Mϕ and having known immunomodulatory activity, we show here that these receptors do not mediate the novel, potent anti-inflammatory effect displayed by hBD3. In contrast to the assumed pro-inflammatory effect of hBD3 summarised above, we show here that synthetic Amino acid hBD3 inhibits production of TNF-α by the human myelomonocytic cell line THP-1 in a concentration-dependent manner (Fig. 1A). The effect was maximal at 2.5 μg/mL, and comparable in magnitude
to the cationic antimicrobial peptide LL37, which is a known immunomodulatory peptide 16–18. This same effect was also evident using human peripheral blood monocyte derived Mϕ (Fig. 1B). Treatments did not affect cell viability as MTT assay measurements were comparable between treated cells and untreated controls. Addition of hBD3 to the mouse Mϕ cell line RAW264.7 also led to inhibition of TNF-α and IL-6 production (Fig. 1C and D). In our experimental settings hBD3 did not induce TNF-α or IL-6, in contrast to the recent report that this defensin activates monocytes and myeloid dendritic cells via TLR1/2, up-regulating the co-stimulatory molecules CD80, CD86 and CD40 12. We observe our anti-inflammatory effect with 5 μg/mL (∼1 μM) of synthetic hBD3 by directly measuring the attenuation of pro-inflammatory cytokine production, whereas Funderburg et al observe their effects on co-stimulatory molecules with 20 μg/mL of recombinant hBD3 (and do not measure pro-inflammatory cytokines). We did, however, observe a slight increase in TNF-α with hBD3 at 10 μg/mL but only in RAW264.7 cells (Fig.
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