The Role of HSP70 Heat Shock Proteins in the Pathogenesis and Treatment of Inflammatory Bowel Diseases

Abstract

Heat shock proteins (HSPs) represent an important element in the body's defense against various damaging factors. The probably also play an important role in the pathogenesis and treatment of several diseases, including autoimmune pathology and neoplasms. Recently, several investigators have focused their attention on the involvement of the HSP70 protein family in the morbid process of inflammatory bowel diseases (IBD). The HSP70 family of is represented by two distinct forms of protein, the HSP72 protein (also known as the HSP70.1 protein), the expression of which is clearly increased in conditions of stress; and the HSP73 (or HSC73) protein, which manifests stable expression. HSP70 proteins are present in the colorectal epithelium. In patients with inflammatory bowel diseases, their expression in significantly increased during the active stage of the disease. In experimental studies, overexpression of HSP70 was found to prevent the development of inflammatory process in the large intestinal mucosa provoked by various damaging factors. In physiological conditions, various mechanisms are considered to be responsible for an increased expression of HSP70. One of them involves lymphocyte activity and the production of cytokines (mainly IL-2). Another suggested mechanism involves the presence of bacteria in the large intestine, including both physiological flora (Lactobacillus GG, Bacteroides fragilis) and pathogenic bacteria (Salmonella, Escherichia coli). HSP70 expression is probably also increased by physical activity. There is also a potential for pharmacological stimulation of HSP70 expression, linked (for example) to geranylgeranylacetone, polaprezinc and mesalazine. Thus, augmentation of HSP70 expression may become a new element in IBD therapy (Adv Clin Exp Med 2015, 24, 3, 525-530).

Physiological regulation of the heat shock response by glutamine: implications for chronic low-grade inflammatory diseases in age-related conditions

“…IBD includes Crohn's disease, ulcerative colitis, and the consequent intolerance to certain components of diet (e.g., gluten and lactose). If, on the one hand, protein quality control is not, at present, definitely ascribed as causal or result of chronic IBD, both physiological and pharmacological maneuvers leading to the overexpression of protein chaperones, which avoid the formation of protein aggregates and consequent chronic inflammation, have been found to prevent the development of inflammatory process in the large intestinal mucosa provoked by various damaging factors [32]. In this regard, diet is an extremely important factor, since gut microbiota strongly influences the physiology of the gastrointestinal tract, being dramatically affected by what one chronically eats [33].…”

“…Conversely, the protective role of iHSP70 against colitis is associated to its suppressive effect on the expression of pro-inflammatory cytokines [144]. In addition, overexpression of HSP70 was found to prevent the development of inflammatory processes in the large intestinal mucosa provoked by various damaging factors [32].…”

“…Aged people tend to present an array of intestinal dysfunctions, including those associated with gut mucosa transport and dysbiosis [31][32][33]. Since glutamine is of absolute requirement as a fuel substrate for the enterocyte, intestinal utilization of glutamine is important for maintaining the integrity of the intestinal barrier, with subsequent prevention of bacterial translocation and, through stimulation of the gut-associated immune system, prevention of gut barrier atrophy.…”

“…Additionally, intestinal malabsorption of glutamine has been referred to as causal to the ineffectiveness of oral glutamine treatment of obese insulin-resistant mice [311]. If, on the one hand, HSP70 expression is not definitely ascribed as causal or result of chronic inflammatory bowel diseases, overexpression of HSP70 was found to prevent the development of inflammatory process in the large intestinal mucosa provoked by various damaging factors [32]. Corroborating this viewpoint is the finding that combined glutamine and arginine administration is able to decrease pro-inflammatory cytokine production by biopsies from Crohn's patients, this being associated with suppression of NF-κB-and p38/ MAPK-based inflammatory pathways [312].…”

“…Since intestinal dysfunctions are commonly found in the elderly that hamper the ability of aged people to maintain a good nutritional state [31][32][33], more efficient ways to deliver glutamine into the circulation have been permanently being investigated. In this regard, the excellent effects of glutamine dipeptides on glutamine availability have been attributed to the fact that enterocytes have a more efficient transport mechanism for the absorption of dipeptides and tripeptides than for the absorption of free amino acids [316].…”