IL-8 and p53 are inversely regulated through JNK, p38 and NF-kappaB p65 in HepG2 cells during an inflammatory response.
OBJECTIVE
It is reported that Nuclear factor-kappaB (NF-kappaB) activation is dysregulated in chronic inflammatory diseases like psoriasis, rheumatoid arthritis and cancer, resulting in an over expression of pro-inflammatory cytokines and an inhibition of apoptosis. We studied NF-kappaB activation and the induction of interleukin 8 (IL-8) and p53 gene expression in an interleukin 1beta (IL-1beta) stimulated HepG2 cell line.


METHODS
NF-kappaB induced IL-8 and p53 protein production was studied using specific siRNA, an IkappaB kinase 2 inhibitor, and mitogen activated protein kinase (MAPK) inhibitors. Results were analyzed by different techniques including Western blotting and ELISA.


RESULTS
IL-1beta induced both the IL-8 and p53 mRNA expression and protein production of IL-8, but not p53. Knockdown of NF-kappaB p65 expression with siRNA strongly reduced IL-8 production and significantly induced protein levels of p53. An IkappaB kinase 2 inhibitor, sc514, also strongly reduced IL-8 and significantly induced p53 protein levels. Using three MAPK inhibitors we showed that p38 MAPK and JNK dependent mechanisms are involved in the regulation of the IL-8 and p53 protein expression.


CONCLUSIONS
Our results indicate that IL-8 and p53 protein expression is regulated through inverse activation of the p38 MAPK and the JNK pathways and the NF-kappaB p65 expression.
Rasmussen
M K
MK
Department of Dermatology, Aarhus University Hospital, P. Orumsgade 11, 8000 Aarhus, Denmark.
Iversen
L
L
Johansen
C
C
Finnemann
J
J
Olsen
L S
LS
Kragballe
K
K
Gesser
Borbala
B
D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation; D016209:Interleukin-8 / Q000502:physiology*; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D013997:Time Factors; D051996:Transcription Factor RelA / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D004791:Enzyme Inhibitors; D016209:Interleukin-8; D016328:NF-kappa B; C498143:RELA protein, human; D034741:RNA, Small Interfering; D051996:Transcription Factor RelA; D016159:Tumor Suppressor Protein p53; D048051:p38 Mitogen-Activated Protein Kinases