Abstract
The goal of this study was to elucidate the action of the CD28 mimetic peptide p2TA (AB103) that attenuates an excessive inflammatory response in mitigating radiation-induced inflammatory injuries. BALB/c and A/J mice were divided into four groups: Control (C), Peptide (P; 5 mg/kg of p2TA peptide), Radiation (R; total body irradiation with 8 Gy γ-rays), and Radiation + Peptide (RP; irradiation followed by p2TA peptide 24 h later). Gastrointestinal tissue damage was evaluated by analysis of jejunum histopathology and immunohistochemistry for cell proliferation (Cyclin D1) and inflammation (COX-2) markers, as well as the presence of macrophages (F4/80). Pro-inflammatory cytokines IL-6 and KC as well as fibrinogen were quantified in plasma samples obtained from the same mice. Our results demonstrated that administration of p2TA peptide significantly reduced the irradiation-induced increase of IL-6 and fibrinogen in plasma 7 days after exposure. Seven days after total body irradiation with 8 Gy of gamma rays numbers of intestinal crypt cells were reduced and villi were shorter in irradiated animals compared to the controls. The p2TA peptide delivery 24 h after irradiation led to improved morphology of villi and crypts, increased Cyclin D1 expression, decreased COX-2 staining and decreased numbers of macrophages in small intestine of irradiated mice. Our study suggests that attenuation of CD28 signaling is a promising therapeutic approach for mitigation of radiation-induced tissue injury.
Highlights
Exposure to ionizing radiation (IR) promotes both inflammatory reactions and immune system dysbalance
Short peptides can prevent Cluster of differentiation 28 (CD28) signaling induced by superantigen toxins [7], [8] or streptococcal infection [9]. p2TA is an octapeptide mimetic of the CD28 homodimer interface that prevents the engagement of CD28 by superantigens in vivo, averting T cell activation leading to protection from lethal toxic shock caused by an excessive inflammatory response [8], [10]
Animals Eight animals each were exposed to 8 Gy of total-body irradiation; four of them were injected with p2TA peptide 24 h later in order to evaluate whether p2TA can mitigate the effects of radiation
Summary
Exposure to ionizing radiation (IR) promotes both inflammatory reactions and immune system dysbalance. Radiation-induced acute inflammatory responses have been shown to activate multiple pro-inflammatory cytokines and inhibit anti-inflammatory cytokines; cytokines are often used to modulate the effects of IR [1]. The excessive gastrointestinal (GI) inflammatory response that occurs following radiation is considered one of the drivers of multiple organ failure induced by IR [2], [3]. Modulating radiation induced inflammatory reactions, especially in the GI tract can have significant effects on the rest of the organism. P2TA ( designated AB103) is an octapeptide mimetic of the CD28 homodimer interface that prevents the engagement of CD28 by superantigens in vivo, averting T cell activation leading to protection from lethal toxic shock caused by an excessive inflammatory response [8], [10]. Because p2TA attenuates the CD28 cascade and inflammatory cytokine response, we hypothesized that it may be PLOS ONE | www.plosone.org p2TA Protects against Radiation Gastrointestinal Injury useful as a mitigator of radiation effects associated with inflammation
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