The role of Haptoglobin and its related protein, Zonulin, in inflammatory bowel disease

Abstract

Crohn's disease (CD) and ulcerative colitis (UC), collectively called inflammatory bowel disease (IBD), are immune-mediated conditions characterized by a chronic inflammation of the gut. Their precise etiology is unknown, although an increased intestinal permeability has been shown to play a central role in the pathogenesis of IBD. The intestinal epithelium provides the largest interface between the external environment and the host, and is thus a crucial regulation site of innate and adaptive immunity. Zonulin is one of the few known physiological mediators of paracellular intestinal permeability. It was found upregulated in different immune diseases like Celiac disease and Type 1 Diabetes (T1D). Recently, human zonulin was identified as prehaptoglobin-2 (pre-HP2) which before only had been regarded as the inactive precursor for HP2. Haptoglobin (HP) is a hemoglobin-binding protein with immunomodulatory properties. Its gene harbors a common polymorphism with 2 different alleles: HP1 and HP2. Allele HP2 and genotype HP22 has been shown to be overrepresented in different immune diseases like Rheumatoid Arthritis (RA), Systemic Lupus Erythematosus (SLE) and T1D, and has also been found to be more frequent in patients with IBD (UC and CD) than in healthy controls. In order to get some clues about the mechanism of action of HP(2) in IBD pathogenesis, we here review the current state of knowledge about zonulin and haptoglobin structure and function, and their plausible role in immune mediated diseases with an emphasis on IBD.

Dietary intervention with serum-derived bovine immunoglobulins protects barrier function in a mouse model of colitis

“…Other histological alterations reported here in the 8-wk-old KO mice are analogous to those described in 6-to 11-wk-old (5) and 12-wk-old animals (34). An impaired intestinal barrier allows unprocessed luminal antigens to interact with the mucosal immune system, thereby leading to an abnormal immune response (40). The situation is worsened when there is low or no expression of P-gp, because this increases the risk of developing colitis (34,36).…”

Toward Omics-Based, Systems Biomedicine, and Path and Drug Discovery Methodologies for Depression-Inflammation Research

“…haptoglobin, albumin and transferrin [2]. Nevertheless, most research focused on CRP despite the important role of for example haptoglobin in the immune response, bacterial translocation and O&NS pathways and a possible association between haptoglobin polymorphism (Hp1 and Hp2) and depression [2,[37][38][39].…”

“…Induction of the TRYCAT pathway through CMI, inflammatory and oxidative processes confers protection against the primary immune-inflammatory and oxidative responses through lowered levels of tryptophan and increased levels of TRYCATs, such as kynurenine, and kynurenic and xanthurenic acid [54,55]. Some acute phase proteins, including haptoglobin, have antiinflammatory effects and act as antioxidants [37]. Elevated IL-6 levels may be anti-inflammatory and protective by increasing IL-1RA, IL-10 and glucocorticoid production [42,53].…”

Endoplasmic Reticulum Stress and Apoptosis Triggered by Sub-Chronic Lead Exposure in Mice Spleen: a Histopathological Study

“…In blood plasma, Hp binds free haemoglobin released from erythrocytes with high affinity and thereby inhibits its oxidative activity. The Hp-haemoglobin complex will then be removed by the reticuloendothelial system, mostly in the spleen [46]. Hp has also been shown to modulate several aspects of the innate and adaptive immune response and to have antiinflammatory properties [47,48].…”