Abstract
BackgroundPancreatitis-associated protein (PAP) is a pancreatic secretory protein belongs to the group VII of C-type lectin family. Emerging evidence suggests that PAP plays a protective effect in inflammatory diseases. In the present study, we newly identified a 16-amino-acid peptide (named PAPep) derived from C-type lectin-like domain (CTLD) of human PAP with potent anti-inflammatory activity using both in vivo and in vitro assays.Methodology/Principal FindingsWe assessed the anti-inflammatory effect of PAPep on endotoxin-induced uveitis (EIU) in rats and demonstrated that intravitreal pretreatment of PAPep concentration-dependently attenuated clinical manifestation of EIU rats, reduced protein leakage and cell infiltration into the aqueous humor (AqH), suppressed tumor necrosis factor (TNF)-α, interleukin (IL)-6, intercellular adhesion molecule-1 (ICAM-1) and monocyte chemoattractant protein (MCP)-1 production in ocular tissues, and improved histopathologic manifestation of EIU. Furthermore, PAPep suppressed the LPS-induced mRNA expression of TNF-α and IL-6 in RAW 264.7 cells, inhibited protein expression of ICAM-1 in TNF-α-stimulated human umbilical vein endothelial cells (HUVECs) as well as U937 cells adhesion to HUVECs. Western blot analysis in ocular tissues and different cell lines revealed that the possible mechanism for this anti-inflammatory effect of PAPep may depend on its ability to inhibit the activation of NF-kB signaling pathway.Conclusions/SignificanceOur studies provide the first evidence that the sequence of PAPep is within the critically active region for the anti-inflammatory function of PAP and the peptide may be a promising candidate for the management of ocular inflammatory diseases.
Highlights
Uveitis is a relatively common intraocular inflammatory disease and one of the most damaging ocular conditions that its recurrent nature could lead to cataract, macular edema, glaucoma, and, destruction of the intraocular tissues and blindness [1]
U937 Cells Adhesion to human umbilical vein endothelial cells (HUVECs) Is intercellular adhesion molecule-1 (ICAM-1)-dependent As the expression of adhesion molecules on endothelial cells is a prerequisite for adhesion of leukocytes and monocytes, we investigated the effect of PAPep on tumor necrosis factor (TNF)-a-induced ICAM-1 expression in HUVECs
We first preliminarily investigate the whole domain by sequence alignment, second structure analysis and bioinformatics analysis to theoretically screen out the most promising regions that might within the key active region of human Pancreatitis-associated protein (PAP)
Summary
Uveitis is a relatively common intraocular inflammatory disease and one of the most damaging ocular conditions that its recurrent nature could lead to cataract, macular edema, glaucoma, and, destruction of the intraocular tissues and blindness [1]. Present pharmacological treatment for uveitis primarily includes nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids and immunosuppressive agents such as cyclosporin A [3]. These drugs do not completely control the disease in many patients and long term application of these drugs may result in multiple adverse effects such as cataract, glaucoma, susceptibility to microbial infection and nephrotoxicity [4,5,6,7]. We newly identified a 16-amino-acid peptide (named PAPep) derived from C-type lectin-like domain (CTLD) of human PAP with potent anti-inflammatory activity using both in vivo and in vitro assays
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