Distinct differences in the responses of the human pancreatic β-cell line EndoC-βH1 and human islets to proinflammatory cytokines. Am J Physiol Regul Integr Comp Physiol 2015 Sep;309(5):R525-34
Date
06/19/2015Pubmed ID
26084699Pubmed Central ID
PMC4591379DOI
10.1152/ajpregu.00544.2014Scopus ID
2-s2.0-84940639041 (requires institutional sign-in at Scopus site) 35 CitationsAbstract
While insulinoma cells have been developed and proven to be extremely useful in studies focused on mechanisms controlling β-cell function and viability, translating findings to human β-cells has proven difficult because of the limited access to human islets and the absence of suitable insulinoma cell lines of human origin. Recently, a human β-cell line, EndoC-βH1, has been derived from human fetal pancreatic buds. The purpose of this study was to determine whether human EndoC-βH1 cells respond to cytokines in a fashion comparable to human islets. Unlike most rodent-derived insulinoma cell lines that respond to cytokines in a manner consistent with rodent islets, EndoC-βH1 cells fail to respond to a combination of cytokines (IL-1, IFN-γ, and TNF) in a manner consistent with human islets. Nitric oxide, produced following inducible nitric oxide synthase (iNOS) expression, is a major mediator of cytokine-induced human islet cell damage. We show that EndoC-βH1 cells fail to express iNOS or produce nitric oxide in response to this combination of cytokines. Inhibitors of iNOS prevent cytokine-induced loss of human islet cell viability; however, they do not prevent cytokine-induced EndoC-βH1 cell death. Stressed human islets or human islets expressing heat shock protein 70 (HSP70) are resistant to cytokines, and, much like stressed human islets, EndoC-βH1 cells express HSP70 under basal conditions. Elevated basal expression of HSP70 in EndoC-βH1 cells is consistent with the lack of iNOS expression in response to cytokine treatment. While expressing HSP70, EndoC-βH1 cells fail to respond to endoplasmic reticulum stress activators, such as thapsigargin. These findings indicate that EndoC-βH1 cells do not faithfully recapitulate the response of human islets to cytokines. Therefore, caution should be exercised when making conclusions regarding the actions of cytokines on human islets when using this human-derived insulinoma cell line.
Author List
Oleson BJ, McGraw JA, Broniowska KA, Annamalai M, Chen J, Bushkofsky JR, Davis DB, Corbett JA, Mathews CEAuthor
John A. Corbett PhD Chair, Professor in the Biochemistry department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsCell Death
Cell Line, Tumor
Cyclooxygenase 2
Cytokines
Energy Metabolism
HSP70 Heat-Shock Proteins
Humans
Inflammation Mediators
Insulin
Insulin-Secreting Cells
Insulinoma
Interferon-gamma
Interleukin-1beta
Islets of Langerhans
Male
Nitric Oxide
Nitric Oxide Synthase Type II
Pancreatic Neoplasms
Phenotype
Rats, Sprague-Dawley
Signal Transduction
Time Factors
Tissue Culture Techniques
Tumor Necrosis Factor-alpha
