HIF-1α regulates epithelial inflammation by cell autonomous NFκB activation and paracrine stromal remodeling

Abstract

IntroductionInflammation assumes many forms, such as the response to acute epithelial barrier injury, acute microbial infection, recurrent tissue nondestructive lesions as in psoriasis, chronic tissue destruction as seen in a myriad of autoimmune or innate inflammatory diseases, or chronic microbial/viral infestations and infections. Chronic inflammation with attendant microenvironmental alterations, resulting from growth factor, chemokine, cytokine secretion, and reactive oxygen species enrichment, also provides a fertile soil for de novo development of epithelial cancer. 1,2 Elucidation of the mechanisms of inflammatory modulation by epithelial cells is an emergent focus of investigation. Models of epithelial elaboration of specific inflammatory chemokines, cytokines, or growth factors have shed light on the roles of specific signaling networks in disease. In contrast, the concept that transcription factors regulate production of a repertoire of inflammatory chemokines and cytokines by epithelial cells is relatively new. 3,4 Here we demonstrate that gain of function of the transcription factor hypoxia inducible factor-1 (HIF-1), signaling indirectly through nuclear factor [kappa2]B (NFB), can "prime" and remodel the local stromal environment to affect an augmented, enhanced responsiveness "hyper-responsiveness" to an inflammatory stimulus. This may be yet another mechanism, broadcast from the epithelial cells themselves, by which both HIF-1 and NFB conspire to increase the severity of inflammatory diseases and carcinogenic progression.HIF-1 is a fundamental mediator of cellular adaptation to hypoxia, activating metabolic and signaling pathways promoting cell survival. HIF-1 consists of the oxygen-sensitive subunit HIF-1␣ and the constitutively expressed HIF-1␤ subunit. In normoxia, the alpha subunit is hydroxylated in position 402 and 564 by 3 prolyl hydroxylase enzymes (PHD) 1 to 3. These modifications allow interaction between HIF-1␣ and the von Hippel-Lindau protein, targeting HIF-1␣ for proteasomal degradation. In hypoxia, PHD activity is decreased, preventing HIF-1␣ degradation. 5,6 When HIF-1␣ levels increase, functional HIF-1 regulates transcription at hypoxia response elements of target gene enhancers, up-regulating genes involved in energy metabolism and angiogenesis. 7 HIF-1␣ protein synthesis can be regulated in an O 2 -independent manner by activation of the phosphatidylinositol 3-kinase and ERK mitogen-activated kinase pathways that are either physiologically stimulated by cognate growth factors or cytokines or activated by mutation. Thus, proinflammatory cytokines, interleukin-1␤ and tumor necrosis factor␣ (TNF␣) have each been shown to stabilize HIF-1␣ protein, suggesting that HIF-1␣ functions can be recruited by tissue inflammation. [8][9][10] The concept The online version of this article contains a data supplement.The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked ''advertisement'' in a...

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