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ATF3 Regulation of IL6 in Response to Acute Ozone Exposure
Author(s) -
Sinha Utkarshna,
Mishra Vikas,
Cabello Noe,
DiAngelo Susan,
Chroneos Zissis,
Silveyra Patricia
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.863.2
Subject(s) - stat3 , atf3 , inflammation , interleukin 6 , chemistry , immunology , medicine , ozone , endocrinology , andrology , biology , signal transduction , gene expression , promoter , gene , biochemistry , organic chemistry
Ozone causes lung inflammation, which can lead to acute lung injury and compromise innate pulmonary immunity. Former research showed that female mice respond more adversely to ozone, and express increased pro‐inflammatory cytokines such as interleukin 6 (IL6). IL6 activates the JAK/STAT pathway and is regulated by activating transcription factor 3 (ATF3). Here, we studied whether ATF3 regulates sex‐differences IL6 expression and associated intracellular signaling mechanisms in response to ozone. For this, wild type (WT) and ATF3 knockout (KO) mice (n=7 KO males, n=11 WT males, n=15 KO females, n=27 WT females) were exposed to ozone (2ppm) or filtered air (FA) for 3h. Lungs were harvested 4h post‐exposure and RNA and protein were extracted. Gene expression of ATF3, IL6, JAK2 and STAT3 was analyzed by Real Time PCR, and Western Blotting was used to evaluate STAT3, p‐STAT3(Y705), p‐STAT3(S727), NFkB, and AKT1 protein expression. We found that in response to ozone, only female WT mice had significantly higher levels of ATF3. All females showed higher JAK2 levels in FA and ozone than males, and all females exposed to ozone had significantly higher IL6 levels than FA. ATF3 KO females had lower IL6 levels than WT females after ozone, but not after FA. In contrast, all ATF3 KO males had significantly higher IL6 levels than WT males. In all WT mice, ozone exposure increased phosphorylation of STAT3(Y705). The ATF3 KO male mice exposed to FA also had increased p‐STAT3(Y705) vs. WT. These results suggest that ATF3 mediates inhibition of IL6 expression in male mice, but promotes IL6 expression in female mice exposed to ozone. The observed sex differences in ATF3 regulation of IL6 may involve signaling pathways mediated by phosphorylation of STAT3 at Y705.