TY  - JOUR
A1  - Namgaladze, Dmitry
A1  - Snodgrass, Ryan G.
A1  - Angioni, Carlo
A1  - Großmann, Nina
A1  - Dehne, Nathalie
A1  - Geisslinger, Gerd
A1  - Brüne, Bernhard
T1  - AMP-activated protein kinase suppresses arachidonate 15-lipoxygenase expression in interleukin 4-polarized human macrophages
T2  - Journal of biological chemistry
N2  - Macrophages respond to the Th2 cytokine IL-4 with elevated expression of arachidonate 15-lipoxygenase (ALOX15). Although IL-4 signaling elicits anti-inflammatory responses, 15-lipoxygenase may either support or inhibit inflammatory processes in a context-dependent manner. AMP-activated protein kinase (AMPK) is a metabolic sensor/regulator that supports an anti-inflammatory macrophage phenotype. How AMPK activation is linked to IL-4-elicited gene signatures remains unexplored. Using primary human macrophages stimulated with IL-4, we observed elevated ALOX15 mRNA and protein expression, which was attenuated by AMPK activation. AMPK activators, e.g. phenformin and aminoimidazole-4-carboxamide 1-β-d-ribofuranoside inhibited IL-4-evoked activation of STAT3 while leaving activation of STAT6 and induction of typical IL-4-responsive genes intact. In addition, phenformin prevented IL-4-induced association of STAT6 and Lys-9 acetylation of histone H3 at the ALOX15 promoter. Activating AMPK abolished cellular production of 15-lipoxygenase arachidonic acid metabolites in IL-4-stimulated macrophages, which was mimicked by ALOX15 knockdown. Finally, pretreatment of macrophages with IL-4 for 48 h increased the mRNA expression of the proinflammatory cytokines IL-6, IL-12, CXCL9, and CXCL10 induced by subsequent stimulation with lipopolysaccharide. This response was attenuated by inhibition of ALOX15 or activation of AMPK during incubation with IL-4. In conclusion, limiting ALOX15 expression by AMPK may promote an anti-inflammatory phenotype of IL-4-stimulated human macrophages.
KW  - AMP-activated kinase (AMPK)
KW  - arachidonic acid (AA)
KW  - gene expression
KW  - inflammation
KW  - transcription
Y1  - 2021
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/77159
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-771598
SN  - 0021-9258
VL  - 290.2015
IS  - 40
SP  - 24484
EP  - 24494
PB  - American Society for Biochemistry and Molecular Biology Publications
CY  - Bethesda, Md
ER  -