IL-4 upregulates IL-1-induced chemokine gene expression in bone marrow stromal cells by enhancing NF-kB activation.
Bone marrow stromal cells play a critical role in the proliferation and differentiation of hematopoietic stem and progenitor cells by secreting numerous hematopoietic growth factors and colony-stimulating factors (CSFs). We have previously reported that monocyte chemotactic protein-1 (MCP-1 or MCP-1/JE) and interferon-inducible protein 10 KD (IP-10) are both induced in murine bone marrow stromal cell line +/(+)-1.LDA11 upon stimulation with various inflammatory agents, including IL-1 alpha, IFN-gamma, TNF-alpha, or LPS. In addition, the expression of MCP-1/JE and IP-10 mRNA by these inducers is potentiated by IL-4 and TGF-beta 1. In the present study we have investigated the mechanism of IL-4-mediated upregulation of MCP-1/JE gene expression. Our results of nuclear run-on experiments show that IL-4 enhances the IL-1-induced transcription of MCP-1/JE gene. Because the transcription of genes is regulated by DNA binding nuclear factors and binding sites for transcription factors AP-1 and SP-1, and NF-kB in the enhancer region of MCP-1/JE have been demonstrated, we examined the effect of IL-4 on the levels of these factors in stromal cells stimulated with IL-1. Whereas AP-1 and SP-1 are constitutively expressed in stromal cells, NF-kB is detected only after stimulation with IL-1. Furthermore, while unable to induce the activation of NF-kB alone, IL-4 enhanced the activation of NF-kB by IL-1. Taken together, these data suggest that upregulation of NF-kB may be the mechanism by which IL-4 increases the transcription of MCP-1/JE gene resulting in overabundance of the chemokine mRNA.
Pindolia
K R
KR
Department of Medicine, Henry Ford Hospital, Detroit, Michigan 48202, USA.
Noth
C J
CJ
Xu
Y X
YX
Janakiraman
N
N
Chapman
R A
RA
Gautam
S C
SC
D000818:Animals; D001853:Bone Marrow / Q000378:metabolism*; D002460:Cell Line; D018932:Chemokine CCL2 / Q000235:genetics / Q000502:physiology; D018925:Chemokines / Q000235:genetics* / Q000378:metabolism; D004357:Drug Synergism; D005786:Gene Expression Regulation / Q000187:drug effects; D007375:Interleukin-1 / Q000494:pharmacology / Q000502:physiology*; D015847:Interleukin-4 / Q000502:physiology*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis; D017154:Stromal Cells / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects
D018932:Chemokine CCL2; D018925:Chemokines; D007375:Interleukin-1; D016328:NF-kappa B; D012333:RNA, Messenger; D015847:Interleukin-4