Differential functional genomic effects of anti-inflammatory phytocompounds on immune signaling.
BACKGROUND
Functional comparative genomic analysis of the cellular immunological effects of different anti-inflammatory phytocompounds is considered as a helpful approach to distinguish the complex and specific bioactivities of candidate phytomedicines. Using LPS-stimulated THP-1 monocytes, we characterize here the immunomodulatory activities of three single phytocompounds (emodin, shikonin, and cytopiloyne) and a defined phytocompound mixture extracted from Echinacea plant (BF/S+L/Ep) by focused DNA microarray analysis of selected immune-related genes.


RESULTS
Shikonin and emodin significantly inhibited the early expression (within 0.5 h) of approximately 50 genes, notably cytokines TNF-α, IL-1β and IL-4, chemokines CCL4 and CCL8, and inflammatory modulators NFATC3 and PTGS2. In contrast, neither cytopiloyne nor BF/S+L/Ep inhibited the early expression of these 50 genes, but rather inhibited most late-stage expression (~12 h) of another immune gene subset. TRANSPATH database key node analysis identified the extracellular signal-regulated kinase (ERK) 1/2 activation pathway as the putative target of BF/S+L/Ep and cytopiloyne. Western blot confirmed that delayed inactivation of the ERK pathway was indeed demonstrable for these two preparations during the mid-stage (1 to 4 h) of LPS stimulation. We further identified ubiquitin pathway regulators, E6-AP and Rad23A, as possible key regulators for emodin and shikonin, respectively.


CONCLUSIONS
The current focused DNA microarray approach rapidly identified important subgenomic differences in the pattern of immune cell-related gene expression in response to specific anti-inflammatory phytocompounds. These molecular targets and deduced networks may be employed as a guide for classifying, monitoring and manipulating the molecular and immunological specificities of different anti-inflammatory phytocompounds in key immune cell systems and for potential pharmacological application.
Chiu
Shao-Chih
SC
Graduate Institute of Immunology, China Medical University, 91 Hsueh-Shih Rd, Taichung 40402, Taiwan.
Tsao
Shan-Wen
SW
Hwang
Pei-Ing
PI
Vanisree
Staniforth
S
Chen
Yi-An
YA
Yang
Ning-Sun
NS
D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D016000:Cluster Analysis; D004642:Emodin / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D005812:Genes, Switch / Q000235:genetics; D023281:Genomics / Q000379:methods*; D005960:Glucosides / Q000494:pharmacology; D006801:Humans; D007109:Immunity / Q000187:drug effects* / Q000235:genetics; D007700:Kinetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D009285:Naphthoquinones / Q000494:pharmacology; D020411:Oligonucleotide Array Sequence Analysis; D010936:Plant Extracts / Q000737:chemistry* / Q000494:pharmacology*; D053279:Polyynes / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics / Q000276:immunology*
D000893:Anti-Inflammatory Agents; D005960:Glucosides; D008070:Lipopolysaccharides; D009285:Naphthoquinones; D010936:Plant Extracts; C520271:cytopiloyne; D053279:Polyynes; C016101:shikonin; D004642:Emodin