Department Name

Differential Maturation of Murine Bone-Marrow Derived Dendritic Cells with Lipopolysaccharide and Tumor Necrosis Factor-α

Abstract:
Dendritic cells (DC) play a key role in the interface between the innate and acquired immune systems. In response to both exogenous as well as endogenous signals, DCs undergo a programmed maturation to become an efficient antigen presenting cell. Yet little is known regarding the differential responses by endogenous versus exogenous stimuli on DC maturation. In the present report, we have compared the phenotypic, functional, and genome-wide expression responses associated with DC maturation by bone marrow derived DCs to either an endogenous danger signal, tumor necrosis factor-α (TNF-α), or a microbial product, bacterial lipopolysaccharide (LPS). Examination of DC cell surface expression as well as cytokine production demonstrated that patterns of DC maturation varied dramatically depending upon the stimulus. Whereas LPS was highly effective at inducing phenotypic and functional maturation, TNF-α exposure produced a phenotypically distinct DC. Gene expression patterns in DCs six and 24 hours after LPS and TNF-α exposure revealed that these activation signals produce fundamentally different genomic responses. Supervised analysis revealed that the expression of 929 probe sets discriminated among the treatment groups, and the patterns of gene expression in TNF-α stimulated DCs were more similar to unstimulated cells at both six and 24 hours post stimulation than to LPS stimulated cells at the same time points. These findings reveal that DCs are capable of a varying phenotypic response to different antigens and endogenous signals. 

Manuscript	Submitted to Infection and Immunity
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Tables	1  Phenotypic changes to LPS and mTNF-α stimulation in DCs generated from bone marrow progenitors using GM-CSF alone.   2  List of genes with a known GO identifier contained in bin A (as a group, uniquely upregulated in LPS stimulated DCs that continues to increase in expression with time).   3  List of genes with a known GO identifier contained in bin B (as a group, uniquely upregulated in LPS stimulated DCs that starts to decrease in expression with time).   4  List of genes with a known GO identifier contained in bin C (as a group, uniquely down regulated in LPS stimulated DCs). 5  Partial list of genes associated with immature DCs and the average ratio of their expression in the LPS and rmTNF-α stimulated DCs (ratio = stimulated average expression at time point 6 or 24 hours / unstimulated average expression at time 6 or 24 hours).   6  Partial list of genes associated with mature DCs and the average ratio of their expression in the LPS and rmTNF-α stimulated DCs (ratio = stimulated average expression at time point 6 or 24 hours / unstimulated average expression at time 6 or 24 hours).