title: Cytokines differentially regulate the synthesis of prostanoid and nitric oxide mediators in tumorigenic versus non-tumorigenic mouse lung epithelial cell lines.
abstract: Studies using transgenic and knockout mice have demonstrated that particular cytokines influence lung tumor growth and identified prostaglandin E2 (PGE2), prostacyclin (PGI2) and nitric oxide (NO) as critical mediators of this process. PGE2 and NO were pro-tumorigenic while PGI2 was antitumorigenic. We describe herein an in vitro experimental approach to examine interactions among cytokines, prostaglandins (PGs) and NO. PGE2, PGI2, and NO levels were assayed in culture media from non-tumorigenic mouse lung epithelial cell lines, their spontaneous transformants and mouse lung tumor-derived cell lines, before or after exposure to the cytokines TNFalpha, IFNgamma and IL1beta, alone and in combination. More PGE2 than PGI2 was produced by neoplastic cells, while the opposite was observed in non-tumorigenic lines. Cytokine exposure magnified the extent of these differential concentrations. The PGE2 to PGI2 ratio was also greater in chemically-induced mouse lung tumors than in adjacent tissue or control lungs, supporting the physiological relevance of this in vitro model. Expression of PG biosynthetic enzymes in these cell lines correlated with production of the corresponding PGs. Cytokine treatment enhanced NO production by inducing the inflammation-associated biosynthetic enzyme, inducible NO synthase (iNOS), but this did not correlate with the neoplastic status of cells. Inhibition of iNOS or cyclooxygenase 2 activity using aminoguanidine or NS-398 respectively, demonstrated that NO did not affect PG production nor did PGs influence NO production. Since lack of iNOS inhibits mouse lung tumor formation, we propose that this is independent of any modulation of PG synthesis in epithelial cells. The similar normal/neoplastic trends in PGE2 to PGI2 ratios both in vitro and in vivo, together with an amplification of this difference upon cytokine exposure, are consistent with the hypothesis that cytokines released during inflammation exacerbate differences in the behavior of neoplastic and normal lung cells.
authors.affiliation: Department of Pharmaceutical Sciences, University of Colorado Health Sciences Center, 4200 East Ninth Avenue, Denver, CO 80262, USA. Lori.Nield@uchsc.edu
authors.forename: Lori D
authors.initials: LD
authors.lastname: Dwyer-Nield
authors.forename: Mary C
authors.initials: MC
authors.lastname: Srebernak
authors.forename: Bradley S
authors.initials: BS
authors.lastname: Barrett
authors.forename: Jinhee
authors.initials: J
authors.lastname: Ahn
authors.forename: Pippa
authors.initials: P
authors.lastname: Cosper
authors.forename: Amy M
authors.initials: AM
authors.lastname: Meyer
authors.forename: Lori R
authors.initials: LR
authors.lastname: Kisley
authors.forename: Alison K
authors.initials: AK
authors.lastname: Bauer
authors.forename: David C
authors.initials: DC
authors.lastname: Thompson
authors.forename: Alvin M
authors.initials: AM
authors.lastname: Malkinson
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic; D016207:Cytokines / Q000502:physiology*; D004847:Epithelial Cells; D007249:Inflammation; D008168:Lung / Q000166:cytology*; D008175:Lung Neoplasms / Q000276:immunology* / Q000503:physiopathology*; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D011453:Prostaglandins / Q000096:biosynthesis* / Q000502:physiology*
chemical_list: D016207:Cytokines; D011453:Prostaglandins; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse