Regulation of lung fibroblast activation by annexin A1.
Annexin-A1 (AnxA1) is a glucocorticoid-induced protein with multiple actions in the regulation of inflammatory cell activation. The contribution of AnxA1 to human cell biology is not well understood. We investigated the contribution of AnxA1 and its receptor, formyl-peptide receptor 2 (FPR2), to the regulation of inflammatory responses in human normal lung fibroblasts (NLF). Silencing constitutive AnxA1 expression in NLF using small interfering RNA (siRNA) was associated with moderate but significant increases in tumor necrosis factor (TNF)-induced proliferation and interleukin (IL)-6 production, accompanied by reduction of ERK and NF-κB activity. AnxA1 regulation of ERK and NF-κB activation was associated with effects on proliferation. Blocking FPR2 using the specific antagonist WRW4 mimicked the effects of AnxA1 silencing on TNF-induced proliferation, IL-6, ERK, and NF-κB activation. AnxA1 silencing also impaired inhibitory effects of glucocorticoid on IL-6 production and on the expression of glucocorticoid-induced leucine zipper (GILZ), but blocking FPR2 failed to mimic these effects of AnxA1 silencing. These data suggest that AnxA1 regulates TNF-induced proliferation and inflammatory responses in lung fibroblasts, via effects on the ERK and NF-κB pathways, which depend on FPR2. AnxA1 also mediates effects of glucocorticoids and GILZ expression, but these effects appear independent of FPR2. These findings suggest that mimicking AnxA1 actions might have therapeutic potential in chronic inflammatory lung diseases.
Centre for Inflammatory Diseases, Southern Clinical School, Monash University Faculty of Medicine Nursing and Health Sciences, Monash Medical Centre, Clayton, Victoria, Australia.
Yuan
Y
Jia
Eric F
EF
Morand
Wuqi
W
Song
Qiang
Q
Cheng
Alastair
A
Stewart
Yuan H
YH
Yang
D017305:Annexin A1 / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D005347:Fibroblasts / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D020868:Gene Silencing; D005938:Glucocorticoids / Q000494:pharmacology; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis; D008168:Lung / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D016328:NF-kappa B / Q000378:metabolism; D011014:Pneumonia / Q000188:drug therapy / Q000378:metabolism; D044042:Receptors, Formyl Peptide / Q000378:metabolism; D044067:Receptors, Lipoxin / Q000378:metabolism; D014157:Transcription Factors / Q000096:biosynthesis; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D017305:Annexin A1; C105101:FPR2 protein, human; D005938:Glucocorticoids; C508600:IL6 protein, human; D015850:Interleukin-6; D016328:NF-kappa B; D044042:Receptors, Formyl Peptide; D044067:Receptors, Lipoxin; C439524:TNF protein, human; C404226:TSC22D3 protein, human; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha