title: Differential regulation of CC chemokine ligand 2 and CXCL8 by antifungal agent nystatin in macrophages.
abstract: The polyene antifungal antibiotic nystatin can interact with cholesterol, thereby altering the composition of the plasma membrane in eukaryotic cells. We investigated whether nystatin influences responses to the infection by inducing expression of chemokines. THP-1 macrophages rarely expressed CC chemokine ligand 2 (CCL2) and CXCL8. However, nystatin dose-dependently increased CCL2 and CXCL8 expression at the mRNA and protein levels. To understand the molecular mechanisms of the antifungal agent, we identified cellular factors activated by nystatin and those involved in nystatin-induced upregulation of CCL2 and CXCL8. Treatment with nystatin resulted in enhanced phosphorylation of Akt, ERK1/2, p38 MAPK, and JNK. Treatment with cholesterol, LY294002, Akt inhibitor IV, U0126, and SP6001250 resulted in abrogation or significant attenuation of nystatin-induced CCL2 expression. Nystatin-mediated CXCL8 expression was attenuated in the presence of Akt inhibitor IV and SP6001250. These results indicate that exposure of human macrophages to nystatin can lead to differential regulation of CCL2 and CXCL8 via the activation of multiple cellular kinases. We propose that upregulation of CCL2 and CXCL8 contributes to pharmacological effects of nystatin.
authors.affiliation: Department of Pharmacology, School of Medicine, Pusan National University, Yangsan 626-870, Republic of Korea.
authors.forename: Do-Hyung
authors.initials: DH
authors.lastname: Kim
authors.forename: Byung-Yong
authors.initials: BY
authors.lastname: Rhim
authors.forename: Seong-Kug
authors.initials: SK
authors.lastname: Eo
authors.forename: Koanhoi
authors.initials: K
authors.lastname: Kim
mesh_terms: D000935:Antifungal Agents / Q000494:pharmacology*; D002460:Cell Line; D018932:Chemokine CCL2 / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism / Q000494:pharmacology; D016209:Interleukin-8 / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism* / Q000382:microbiology; D009761:Nystatin / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
chemical_list: D000935:Antifungal Agents; D018932:Chemokine CCL2; D018836:Inflammation Mediators; D016209:Interleukin-8; D009761:Nystatin
keywords: Akt inhibitor IV; Akti IV; CC chemokine ligand 2; CCL2; CXCL8; ERK1/2; JNK; LPS; MAPK; Macrophages; Nystatin; PI3K; c-Jun N-terminal kinase; extracellular signal-regulated kinase 1 and 2; lipopolysaccharide; mitogen-activated protein kinase; phosphoinositide 3-kinase