NF-kappa B activation mediates the cross-talk between extracellular matrix and interferon-gamma (IFN-gamma) leading to enhanced monokine induced by IFN-gamma (MIG) expression in macrophages.
In intact tissue, the extracellular matrix (ECM) provides support and helps maintain homeostasis but is considered biologically inert. In the setting of inflammation, not only is the ECM the target of inflammation, but its breakdown products modulate the magnitude and quality of an immune response. Fragments of the ECM component hyaluronan (HA) induce macrophage expression of chemokines, cytokines, and growth factors as well greatly enhance IFN-gamma-induced MIG expression. In this report, we demonstrate that the synergistic induction of MIG by HA and IFN-gamma occurs at the level of transcription via NF-kappaB. Using electrophoretic mobility shift assays and reporter assays, we have identified two NF-kappaB sites proximal to the IFN-gamma-responsive element-1 (gammaRE-1) that mediate this effect. Interestingly, our experiments also revealed a critical role for NF-kappaB in mediating IFN-gamma-induced MIG expression independent of HA. These data emphasize the ability of "degraded self" to activate/modify immune responses through the NF-kappaB pathway.
Horton
Maureen R
MR
Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
Boodoo
Sada
S
Powell
Jonathan D
JD
D000818:Animals; D015152:Blotting, Northern; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D054370:Chemokine CXCL9; D019743:Chemokines, CXC / Q000378:metabolism*; D019281:Dimerization; D005109:Extracellular Matrix / Q000378:metabolism*; D006820:Hyaluronic Acid / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins; D007371:Interferon-gamma / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism*; D052002:NF-kappa B p50 Subunit; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012333:RNA, Messenger / Q000378:metabolism; D051996:Transcription Factor RelA; D014162:Transfection
C080810:CXCL9 protein, human; D054370:Chemokine CXCL9; D019743:Chemokines, CXC; D036341:Intercellular Signaling Peptides and Proteins; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; D012333:RNA, Messenger; D051996:Transcription Factor RelA; D007371:Interferon-gamma; D006820:Hyaluronic Acid