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. 2022 Sep;1515(1):196-207.
doi: 10.1111/nyas.14842. Epub 2022 Jun 20.

PI3Kγ is a novel regulator of TNFα signaling in the human colon cell line HT29/B6

Franz-Leonard Klaus  1 , Cornelia Kirsch  1 , Jörg P Müller  2 , Otmar Huber  1   3 , Juliane Reiche  1
Affiliations

PI3Kγ is a novel regulator of TNFα signaling in the human colon cell line HT29/B6

Franz-Leonard Klaus et al. Ann N Y Acad Sci. 2022 Sep.

Abstract

Phosphoinositide 3-kinases (PI3Ks) are a family of enzymes phosphorylating phospholipids in the membrane, thereby, promoting the PI3K/AKT signaling cascade. PI3Ks are involved in a variety of fundamental cellular functions, including tumor necrosis factor α (TNFα)-induced tight junction (TJ) impairment-a hallmark of inflammatory bowel diseases. Most of the studies analyzing the role of class I PI3K signaling in epithelial barrier maintenance did not decipher which of the isoforms are responsible for the observed effects. By using wild-type and PI3Kγ-deficient HT-29/B6 cells, we characterized the functional role of PI3Kγ in these cells under inflammatory conditions. Measurement of the transepithelial electrical resistance and the paracellular flux of macromolecules revealed that monolayers of PI3Kγ-deficient cells, compared with wild-type cells, were protected against TNFα-induced barrier dysfunction. This effect was independent of any PI3K activity because treatment with a pan-PI3K inhibitor did not alter this observation. By immunostaining, we found correlative changes in the distribution of the TJ marker ZO-1. Furthermore, the absence of PI3Kγ reduced the basal level of the pore-forming TJ protein claudin-2. Our study suggests a novel noncanonical, kinase-independent scaffolding function of PI3Kγ in TNFα-induced barrier dysfunction.

Keywords: HT-29/B6 cells; PI3Kγ; TER; TNFα; barrier function; claudin; tight junction.

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