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Background: Matrix metalloproteinase-9 (MMP-9) is an emerging biomarker for several disease conditions, where white blood cell (WBC) count is also elevated. In this study, we examined the relationship between MMP-9 and WBC levels in apparently healthy smoking and non-smoking human subjects. Methods: We conducted a cross-sectional study to assess the relationship of serum MMP-9 with WBC in 383 men and 356 women. Next, we divided the male population (women do not smoke in this population) into three groups: never (n = 243), current (n = 76) and former (n = 64) smokers and compared the group differences in MMP-9 and WBC levels and their correlations within each group. Results: Circulating MMP-9 and WBC count are significantly correlated in men (R2 = 0.13, p<0.001) and women (R2 = 0.19, p<0.001). After stratification by smoking status, MMP-9 level was significantly higher in current smokers (mean ± SE; 663.3±43.4 ng/ml), compared to never (529.7±20.6) and former smokers (568±39.3). WBC count was changed in a similar pattern. Meanwhile, the relationship became stronger in current smokers with increased correlation coefficient of r = 0.45 or R2 = 0.21 (p<0.001) and steeper slope of ß = 1.16±0.30 (p<0.001) in current smokers, compared to r = 0.26 or R2 = 0.07 (p<0.001) and ß = 0.34±0.10 (p<0.001) in never smokers. Conclusions: WBC count accounts for 13% and 19% of MMP-9 variance in men and women, respectively. In non-smoking men, WBC count accounts for 7% of MMP-9 variance, but in smoking subjects, it accounts for up to 21% of MMP-9 variance. Thus, we have discovered a previously unrecognized correlation between the circulating MMP-9 and WBC levels in humans. [ABSTRACT FROM AUTHOR]

Estrogen is traditionally thought to exert genomic actions through members of the nuclear receptor family. Here, we investigated the rapid nongenomic effects of 17β-estradiol (E2) on tumor necrosis factor α (TNF-α) production following lipopolysaccharide (LPS) stimulation in mouse bone marrow-derived macrophages (BMMs). We found that LPS induced TNF-α production in BMMs via phosphorylation of p38 mitogen-activated protein kinase (MAPK). E2 itself did not affect the MAPK pathway, although it attenuated LPS-induced TNF-α production through suppression of p38 MAPK activation. Recently, G protein-coupled receptor 30 (GPR30) was suggested to be a membrane estrogen receptor (mER) that can mediate nongenomic estradiol signaling. We found that BMMs expressed both intracellular estrogen receptors (iER) and mER GPR30. The specific GPR30 antagonist G-15 significantly blocked effects of estradiol on LPS-induced TNF-α production, whereas an iER antagonist did not. Moreover, E2 induced a rapid rise in intracellular free Ca2+ that was due to the influx of extracellular Ca2+ and was not inhibited by an iER antagonist or silencing of iER. Ca2+ influx was also induced by an impermeable E2 conjugated to BSA (E2-BSA), which has been used to investigate the nongenomic effects of estrogen. Consequently, Ca2+, a pivotal factor in E2-stimulated nongenomic action, was identified as the key mediator. The inhibitory effects of E2 on LPS-induced TNF-α production and p38 MAPK phosphorylation were dependent on E2-triggered Ca2+ influx because BAPTA, an intracellular Ca2+ chelator, prevented these effects. Taken together, these data indicate that E2 can down-regulate LPS-induced TNF-α production via blockade of p38 MAPK phosphorylation through the mER-mediated nongenomic Ca2+ signaling pathway in BMMs. [ABSTRACT FROM AUTHOR]