Hyperforin, the active component of St. John's wort, induces IL-8 expression in human intestinal epithelial cells via a MAPK-dependent, NF-kappaB-independent pathway.
St. John's wort is widely used as an herbal antidepressant and is among the top-selling botanical products in the United States. Although St. John's wort has been reported to have minimal side effects compared with other antidepressants, here we show that hyperforin, the active component of St. John's wort, can stimulate interleukin-8 (IL-8) expression in human intestinal epithelia cells (IEC) and primary hepatocytes. Hyperforin is also able to induce expression of mRNA, encoding another major inflammatory mediator--intercellular adhesion molecule-1 (ICAM-1). IEC participate in the intestinal inflammatory process and serve as a first line of defense through bidirectional communication between host and infectious pathogens. Although hyperforin is a potent ligand for the steroid and xenobiotic receptor (SXR), we found that hyperforin induced IL-8 mRNA through an SXR-independent transcriptional activation pathway. IL-8 induction by hyperforin required the activation of AP-1 but not the NF-kappaB transcription factor, thereby distinguishing it from the NF-kappaB-dependent IL-8 induction mediated by tumor necrosis factor alpha (TNFalpha). Further study revealed that extracellular signal-regulated kinase 1 and 2 (ERK1/2) were required for the hyperforin-induced expression of IL-8. Our results suggest a previously unsuspected effect of St. John's wort in modulating the immune and inflammatory responses.
Zhou
Changcheng
C
Department of Developmental and Cell Biology, University of California, Irvine, California 92697-2300, USA.
Tabb
Michelle M
MM
Sadatrafiei
Asal
A
Grün
Felix
F
Sun
Aixu
A
Blumberg
Bruce
B
D000928:Antidepressive Agents / Q000494:pharmacology; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology*; D002460:Cell Line; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D020902:Hypericum / Q000737:chemistry*; D018836:Inflammation Mediators; D016209:Interleukin-8 / Q000235:genetics*; D007413:Intestinal Mucosa / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases; D016328:NF-kappa B / Q000378:metabolism; D010696:Phloroglucinol / Q000031:analogs & derivatives* / Q000494:pharmacology*; D008517:Phytotherapy / Q000009:adverse effects; D015398:Signal Transduction; D013729:Terpenes / Q000494:pharmacology*; D018808:Transcription Factor AP-1 / Q000378:metabolism
D000928:Antidepressive Agents; D001643:Bridged Bicyclo Compounds; D018836:Inflammation Mediators; D016209:Interleukin-8; D016328:NF-kappa B; D013729:Terpenes; D018808:Transcription Factor AP-1; D010696:Phloroglucinol; D020928:Mitogen-Activated Protein Kinases; C001654:hyperforin