Paraoxonase-1 Suppresses Experimental Colitis via the Inhibition of IFN-γ Production from CD4 T Cells

Abstract

Crohn’s disease (CD) is a chronic inflammatory disorder of the gastrointestinal tract, where excessive Th1 cell responses are observed. We performed experiments to identify immunologically bioactive proteins in human plasma and found that paraoxonase (PON)-1, which has esterase activity and is associated with high-density lipoproteins, inhibited the IFN-γ production by both murine and human differentiating Th1 cells. Trinitrobenzene sulfonic acid–induced colitis was attenuated by the administration of PON-1. The beneficial effects of PON-1 were associated with a reduced ratio of IFN-γ–producing CD4 T cells in the mesenteric lymph nodes and decreased production of T cell–related cytokines in the colon. PON-1 inhibited the TCR-induced activation of ERK-MAPK signaling and the nuclear translocation of NF-κB in CD4 T cells. Interestingly, an excessive CD4 T cell response was observed in PON-1–deficient mice under physiological and pathological conditions. Additionally, the efficacy of PON-1 or G3C9-C284A (G3C9), which shows a higher esterase activity than PON-1, on colitis was similar to that of an anti–TNF-α mAb, which is a clinically used CD treatment. Moreover, G3C9 more effectively suppressed CD4+CD45RBhigh cell transfer–induced chronic colitis in mice than did PON-1, and the efficacy of G3C9 against the colitis was similar to that of the anti–TNF-α mAb. Therefore, PON-1 (or G3C9) administration may be clinically beneficial for CD patients.

A single administration of human adipose tissue-derived mesenchymal stromal cells (MSC) induces durable and sustained long-term regulation of inflammatory response in experimental colitis

“…Therefore, we believe that the colitis amelioration after MSC treatment may be correlated with the control of inflammatory responses upon direct or indirect modulation of the recipient's T reg . Yamanishi et al [50] have shown that the induction of forkhead box protein 3 (FoxP3) + CD4 + CD25 + cells improves experimental colitis, corroborating our findings. Moreover, although we have not observed higher expression of FoxP3 in mice treated with MSC, the increase of other markers of T reg is in agreement with the hypothesis that infused MSC may have promoted immunoregulation and controlled the intestinal response in animals with colitis.…”

“…In agreement, MSC administration alleviates TNBSinduced murine colitis by correcting Th1/Th17/T reg imbalances [47]. Yamanishi et al [50] have shown that the induction of forkhead box protein 3 (FoxP3) + CD4 + CD25 + cells improves experimental colitis, corroborating our findings. Therefore, we believe that the colitis amelioration after MSC treatment may be correlated with the control of inflammatory responses upon direct or indirect modulation of the recipient's T reg .…”

Allicin Alleviates Inflammation of Trinitrobenzenesulfonic Acid‐Induced Rats and Suppresses P38 and JNK Pathways in Caco‐2 Cells

“…CD is a T helper 1- (Th1-) mediated disease, with overproduction of IFN- γ and IL-12 [ 14 , 15 ]. It is commonly thought that IL-12-mediated Th1 cell transmural colitis induced by trinitrobenzenesulfonic acid (TNBS) causes immunopathological human CD [ 16 , 17 ].…”

Human Paraoxonase 1 as a Pharmacologic Agent: Limitations and Perspectives

“…The level and the activity of circulating PON1 are also considered as novel biomarkers for the evaluation of these diseases in humans [22–26]. Animals deficient in PON1 have been found to be more susceptible to these disease conditions and the overexpression of h-PON1 or administration of purified PON1 in these animals has been shown to prevent/retard the development of these disease conditions [10, 12, 27–30]. The beneficial role of h-PON1 in OP-poisoning is also well demonstrated.…”