Browsing by Subject "Chemokine CCL2"

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Open Access
Effects of an antisense oligonucleotide inhibitor of C-reactive protein synthesis on the endotoxin challenge response in healthy human male volunteers.
(J Am Heart Assoc, 2014-07-10) Noveck, Robert; Stroes, Erik SG; Flaim, JoAnn D; Baker, Brenda F; Hughes, Steve; Graham, Mark J; Crooke, Rosanne M; Ridker, Paul M
BACKGROUND: C-reactive protein (CRP) binds to damaged cells, activates the classical complement pathway, is elevated in multiple inflammatory conditions, and provides prognostic information on risk of future atherosclerotic events. It is controversial, however, as to whether inhibiting CRP synthesis would have any direct anti-inflammatory effects in humans. METHODS AND RESULTS: A placebo-controlled study was used to evaluate the effects of ISIS 329993 (ISIS-CRPR x) on the acute-phase response after endotoxin challenge in 30 evaluable subjects. Healthy adult males were randomly allocated to receive 6 injections over a 22-day period of placebo or active therapy with ISIS 329993 at 400- or 600-mg doses. Eligible subjects were subsequently challenged with a bolus of endotoxin (2 ng/kg). Inflammatory and hematological biomarkers were measured before and serially after the challenge. ISIS-CRPR x was well tolerated with no serious adverse events. Median CRP levels increased more than 50-fold from baseline 24 hours after endotoxin challenge in the placebo group. In contrast, the median increase in CRP levels was attenuated by 37% (400 mg) and 69% (600 mg) in subjects pretreated with ISIS-CRPR x (P<0.05 vs. placebo). All other aspects of the acute inflammatory response were similar between treatment groups. CONCLUSION: Pretreatment of subjects with ISIS-CRPR x selectively reduced the endotoxin-induced increase in CRP levels in a dose-dependent manner, without affecting other components of the acute-phase response. These data demonstrate the specificity of antisense oligonucleotides and provide an investigative tool to further define the role of CRP in human pathological conditions.
Open Access
RNA-Seq and ChIP-Seq reveal SQSTM1/p62 as a key mediator of JunB suppression of NF-κB-dependent inflammation.
(J Invest Dermatol, 2015-04) Zhang, Xiaoling; Jin, Jane Y; Wu, Joseph; Qin, Xiaoxia; Streilein, Robert; Hall, Russell P; Zhang, Jennifer Y
Mice with epidermal deletion of JunB transcription factor displayed a psoriasis-like inflammation. The relevance of these findings to humans and the mechanisms mediating JunB function are not fully understood. Here we demonstrate that impaired JunB function via gene silencing or overexpression of a dominant negative mutant increased human keratinocyte cell proliferation but decreased cell barrier function. RNA-seq revealed over 500 genes affected by JunB loss of function, which included the upregulation of an array of proinflammatory molecules relevant to psoriasis. Among these were tumor necrosis factor α (TNFα), CCL2, CXCL10, IL6R, and SQSTM1, an adaptor protein involved in nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation. Chromatin immunoprecipitation (ChIP)-Seq and gene reporter analyses showed that JunB directly suppressed SQSTM1 by binding to a consensus AP-1 cis element located around 2 kb upstream of SQSTM1-transcription start site. Similar to JunB loss of function, SQSTM1-overexpression induced TNFα, CCL2, and CXCL10. Conversely, NF-κB inhibition genetically with a mutant IκBα or pharmacologically with pyrrolidine dithiocarbamate (PDTC) prevented cytokine, but not IL6R, induction by JunB deficiency. Taken together, our findings indicate that JunB controls epidermal growth, barrier formation, and proinflammatory responses through direct and indirect mechanisms, pinpointing SQSTM1 as a key mediator of JunB suppression of NF-κB-dependent inflammation.