IFN-gamma and TNF regulate macrophage expression of the chemotactic S100 protein S100A8.
The murine calcium-binding protein S100A8 is a potent chemoattractant for neutrophils and monocytes in vivo and in vitro but may also play a protective role. We show that the kinetics of induction of S100A8 mRNA in elicited murine macrophages (Mac) by LPS, IFN-gamma, and TNF were distinct from the C-C chemokines monocyte chemoattractant protein-1 (MCP-1), macrophage-inflammatory protein-1alpha (MIP-1alpha), and RANTES. Monomeric S100A8 was predominantly secreted. IFN substantially increased S100A8 mRNA levels after 1 h with optimal induction after 12 h; induction by TNF was slower and more sustained. TNF did not up-regulate MCP-1 and MIP-1alpha mRNA in these cells. Luciferase reporter assays confirmed that LPS and IFN induce S100A8 gene transcription and mRNA in LPS-treated Mac showed little decay over 16 h, whereas transcripts induced by IFN and TNF were markedly less stable. Newly synthesized proteins may be required for mRNA transcription and stabilization in response to LPS. S100A9 associates with A8 in neutrophils, but was not coinduced with S100A8. S100A8 gene induction in Mac stimulated with LPS and IFN may be modulated by mobilization of intracellular Ca2+ concentration from distinct intracellular stores and/or the extracellular compartment and by distinct pathways involving protein kinase C and leading to activation of mitogen-activated protein kinase.
Xu
K
K
Cytokine Research Unit, School of Pathology, Faculty of Medicine, University of New South Wales, Sydney, Australia.
Geczy
C L
CL
D000818:Animals; D000943:Antigens, Differentiation / Q000096:biosynthesis; D002135:Calcium-Binding Proteins / Q000096:biosynthesis; D040501:Calgranulin A; D040502:Calgranulin B; D019742:Chemokines, CC / Q000235:genetics / Q000502:physiology; D002630:Chemotactic Factors / Q000096:biosynthesis* / Q000235:genetics; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D005786:Gene Expression Regulation / Q000276:immunology; D007371:Interferon-gamma / Q000502:physiology*; D008262:Macrophage Activation; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D012333:RNA, Messenger / Q000096:biosynthesis; D009418:S100 Proteins; D015533:Transcriptional Activation; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*; D015854:Up-Regulation / Q000276:immunology
D000943:Antigens, Differentiation; D002135:Calcium-Binding Proteins; D040501:Calgranulin A; D040502:Calgranulin B; D019742:Chemokines, CC; D002630:Chemotactic Factors; D012333:RNA, Messenger; D009418:S100 Proteins; C086145:S100a8 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma