Promotion of the inflammatory response in mid colon of complement component 3 knockout mice

Abstract

To determine whether complement component 3 (C3) deficiency affects its receptor downstream-mediated inflammatory response, the current study was undertaken to measure alterations in the inducible nitric oxide synthase (iNOS)‑mediated cyclooxygenase‑2 (COX‑2) induction pathway, inflammasome pathway, nuclear factor-κB (NF-κB) activation, and inflammatory cytokine expressions in the mid colon of C3 knockout (KO) mice. Significant enhancement was observed in expressions of key components of the iNOS‑mediated COX‑2 induction pathway, and in the phosphorylation of mitogen‑activated protein (MAP) kinase members. A similar pattern of increase was also observed in the expression levels of inflammasome proteins in C3 KO mice. Moreover, compared to WT mice, C3 KO mice showed remarkably enhanced phosphorylation of NF-κB and Inhibitor of κB-α (IκB-α), which was reflected in entirety as increased expressions of Tumor necrosis factor (TNF), IL-6 and IL-1α. However, the levels of E-cadherin, tight junction channels and ion channels expressions were lower in the C3 KO mice, although myeloperoxidase (MPO) activity for neutrophils was slightly increased. Taken together, results of the current study indicate that C3 deficiency promotes inflammatory responses in the mid colon of C3 KO mice through activation of the iNOS‑mediated COX‑2 induction pathway, Apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC)-inflammasome pathway and NF-κB signaling pathway, and the enhancement of inflammatory cytokine expressions.

Induction of Apoptosis by Cynaropicrin in Human Colon Cancer Cell Line HCT-116 through the Mitochondria-mediated Apoptotic Pathway

“…Colon cancer cells undergo oxidative damage-arbitrated apoptosis as a result of oxidative stress. Overgeneration or elimination of ROS causes severe damage to the intracellular molecules (Choi et al, 2022). It has been observed that plant-based chemo-preventive agents elevate the generation of ROS and disrupt the homeostasis in cancer cells.…”

Revisiting the relationship between complement and ulcerative colitis

“…A recent study of the effect of C3 deficiency on the colonic inflammatory response revealed that the absence of C3 is associated with the upregulation of proinflammatory cytokines and the downregulation of tight junction channels due to an increase in inducible nitric oxide synthase (iNOS)-mediated cyclooxygenase-2 (COX-2) production. 49 While these data suggest a potential protective role of C3 in both UC patients and animal models of colitis, other studies suggest that C3 may play a pathogenic role. For example, Elisabeth et al found that C3aR contributes to the progression of DSS-induced colitis in BALB/c mice.…”

“…These findings suggest that both extracellular and intracellular C3 fragments can protect the integrity of the intestinal mucosa by promoting intestinal epithelial cells (IECs) proliferation; however, further study is required to assess this. A recent study of the effect of C3 deficiency on the colonic inflammatory response revealed that the absence of C3 is associated with the upregulation of proinflammatory cytokines and the downregulation of tight junction channels due to an increase in inducible nitric oxide synthase (iNOS)‐mediated cyclooxygenase‐2 (COX‐2) production 49 . While these data suggest a potential protective role of C3 in both UC patients and animal models of colitis, other studies suggest that C3 may play a pathogenic role.…”

Contribution of animal models to the mechanistic understanding of Alternative Pathway and Amplification Loop (AP/AL)‐driven Complement‐mediated Diseases

“…However, animal models and complement antagonists which were originally created to investigate innate immunity are also providing insights into other cellular processes; for instance, C3 −/− mice are protected against bone loss in an ovariectomized osteoporosis model, 156 injury-induced neurogenesis, 157,158 pregnancy-associated complications, 159 and inflammatory bowel disease. 160 It is beyond the scope of this review to discuss all these scientific discoveries in detail, so we will concentrate on a few key areas: the controversy of "intracellular complement," metabolism and metabolic disorders and age-related macular degeneration (AMD). suggesting that the original T cell data may be applicable to all cell types.…”