Gliadins induce TNFα production through cAMP-dependent protein kinase A activation in intestinal cells (Caco-2)

Abstract

Celiac disease is an autoimmune enteropathy caused by a permanent intolerance to gliadins. In this study the effects of two gliadin-derived peptides (PA2, PQPQLPYPQPQLP and PA9, QLQPFPQPQLPY) on TNFalpha production by intestinal epithelial cells (Caco-2) and whether these effects were related to protein kinase A (PKA) and/or -C (PKC) activities have been evaluated. Caco-2 cell cultures were challenged with several sets of gliadin peptides solutions (0.25 mg/mL), with/without different activators of PKA or PKC, bradykinin (Brdkn) and pyrrolidine dithiocarbamate (PDTC). The gliadin-derived peptides assayed represent the two major immunodominant epitopes of the peptide 33-mer of alpha-gliadin (56-88) (LQLQPFPQPQLPYPQPQLPYPQPQLPYPQPQPF). Both peptides induced the TNFalpha production triggering the inflammatory cell responses, the PA2 being more effective. The addition of the peptides in the presence of dibutyril cyclic AMP (cAMP), Brdkn or PDTC, inhibited the TNFalpha production. The PKC-activator phorbol 12-myristate 13-diacetate additionally increased the PA2- and PA9-induced TNFalpha production. These results link the gliadin-derived peptides induced TNFalpha production through cAMP-dependent PKA activation, where ion channels controlling calcium influx into cells could play a protective role, and requires NF-kappaB activation.

Identification of Non-HLA Genes Associated with Celiac Disease and Country-Specific Differences in a Large, International Pediatric Cohort

“…It has been previously reported that intestinal PKIA gene expression was increased among patients with untreated celiac disease [ 29 ]. Another study suggests a potential role of cAMP-dependent protein kinase-A activation in the TNF-alpha production by gliadin-derived peptides in intestinal epithelial cells [ 30 ].…”

Prolactin May Be Increased in Newly Diagnosed Celiac Children and Adolescents and Decreases after 6 Months of Gluten-Free Diet

“…Inflammatory cytokines, overall IL-1β, TNF-α, IL-6 and IL-13, released in sites of immune processes, also activate the hypothalamus-inducing release of pituitary PRL [15]. In CD patients, the production of these inflammatory cytokines is increased by the ingestion of gliadin with food [32,33,34,35,36,37,38]. PRL increases the production of interferon-γ by lymphocytes and induces the expression of IL-2 receptors on the surface of lymphocytes [14,39].…”

Harnessing the Power of Microbiome Assessment Tools as Part of Neuroprotective Nutrition and Lifestyle Medicine Interventions

“…For example, in irritable bowel syndrome (IBS), alterations in microbial diversity [ 103 ] are seen in addition to gut-related inflammation as pivotal mediators of endotoxemia, systemic inflammation and neuroinflammation, all of which are documented as contributing factors to cognitive impairment [ 104 , 105 , 106 , 107 , 108 , 109 ]. Many of the foods that abound in Western diets are rich in substances such as gliadins (a component in gluten), which have endotoxin-like effects [ 110 ] that can elicit aberrant immune responses [ 111 , 112 ]. Other proteins such as casein and zein have also been observed to have similar effects in animal models [ 113 ].…”