AMP-activated protein kinase suppresses arachidonate 15-lipoxygenase expression in interleukin 4-polarized human macrophages.
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.
From the Institute of Biochemistry I, Faculty of Medicine and.
Dmitry
D
Namgaladze
From the Institute of Biochemistry I, Faculty of Medicine and.
Ryan G
RG
Snodgrass
Institute of Clinical Pharmacology, Pharmazentrum Frankfurt, Goethe University Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany.
Carlo
C
Angioni
From the Institute of Biochemistry I, Faculty of Medicine and.
Nina
N
Grossmann
From the Institute of Biochemistry I, Faculty of Medicine and.
Nathalie
N
Dehne
Institute of Clinical Pharmacology, Pharmazentrum Frankfurt, Goethe University Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany.
Gerd
G
Geisslinger
From the Institute of Biochemistry I, Faculty of Medicine and b.bruene@biochem.uni-frankfurt.de.
Bernhard
B
Brüne
D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000893:Anti-Inflammatory Agents / Q000737:chemistry; D001093:Arachidonate 15-Lipoxygenase / Q000378:metabolism*; D054357:Chemokine CXCL10 / Q000378:metabolism; D054370:Chemokine CXCL9 / Q000378:metabolism; D020869:Gene Expression Profiling; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D053765:Interleukin-12 Subunit p35 / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism; D008264:Macrophages / Q000201:enzymology*; D009000:Monocytes / Q000166:cytology; D010586:Phagocytes / Q000378:metabolism; D010641:Phenotype; D034741:RNA, Small Interfering / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D013997:Time Factors
D000893:Anti-Inflammatory Agents; C114753:CXCL10 protein, human; C080810:CXCL9 protein, human; D054357:Chemokine CXCL10; D054370:Chemokine CXCL9; C508858:IL12A protein, human; C508598:IL4 protein, human; C508600:IL6 protein, human; D053765:Interleukin-12 Subunit p35; D015850:Interleukin-6; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D015847:Interleukin-4; C515716:ALOX15 protein, human; D001093:Arachidonate 15-Lipoxygenase; D055372:AMP-Activated Protein Kinases
AMP-activated kinase (AMPK); arachidonic acid (AA); gene expression; inflammation; transcription