Activation of cyclic-AMP response element binding protein contributes to adiponectin-stimulated interleukin-10 expression in raw 264.7 macrophages

Adiponectin, an adipokine predominantly secreted from adipose tissue, has potent anti‐inflammatory properties. Although the mechanisms for the anti‐inflammatory properties of adiponectin are not well understood, recent evidence suggests that increased production of interleukin‐10 (IL‐10), a potent immunomodulatory cytokine, is involved in the anti‐inflammatory actions of adiponectin. Globular adiponectin (gAcrp) increased IL‐10 promoter activity and IL‐10 mRNA accumulation in RAW 264.7 macrophages. Deletion of the sequences from −416 and −369 in the IL‐10 promoter, containing a cyclic AMP‐response element (CRE), decreased gAcrp‐induced IL‐10 promoter activation. Treatment of RAW 264.7 macrophages with gAcrp increased the phosphorylation of cyclic AMP response element binding protein (CREB) at Ser133, as well as enhanced the DNA binding activity of CREB. Further, overexpression of a dominant negative form of CREB suppressed gAcrp‐induced transcriptional activation of IL‐10. gAcrp‐stimulated CREB phosphorylation was mediated by the activation of both ERK1/2‐ and cAMP‐dependent protein kinase (PKA)‐dependent pathways. Inhibition of either ERK1/2 or PKA activity prevented gAcrp‐stimulated CREB phosphorylation, as well as gAcrp‐stimulated IL‐10 promoter activation. Taken together, these data identify gAcrp‐stimulated phospho‐CREB as a key transcription factor responsible for gAcrp‐induced IL‐10 promoter activation.