Endogenous interferon-alpha production by differentiating human monocytes regulates expression and function of the IL-2/IL-4 receptor gamma chain.
In vitro monocyte-derived macrophages (MDMac) and synovial fluid macrophages from inflamed joints differ from monocytes in their responses to interleukin 4 (IL-4). While IL-4 can suppress LPS-induced interleukin beta (IL-beta) and tumour necrosis factor alpha (TNF-alpha) production by monocytes, IL-4 can suppress LPS-induced IL-1 beta, but not TNFalpha production by the more differentiated cells. Recently we reported a correlation between the ability of IL-4 to regulate TNFalpha production by monocytes and the expression of the IL-4 receptor gamma chain or gamma common (gamma c chain). Like MDMac, interferon alpha (IFNalpha)-treated monocytes expressed less IL-4 receptor gamma c chain, reduced levels of IL-4-activated STAT6 and IL-4 could not suppress LPS-induced TNFalpha production. In addition, like monocytes and MDMac, IFNalpha-treated monocytes expressed normal levels of the IL-4 receptor alpha chain and IL-4 significantly suppressed LPS-induced IL-1 beta production. With addition of IFNalpha-neutralizing antibodies, the ability of IL-4 to suppress LPS-induced TNFalpha production with prolonged monocyte culture was restored. Detection of IFNalpha in synovial fluids from inflamed joints further implicates IFNalpha in the inability of IL-4 to suppress TNFalpha production by synovial fluid macrophages. This study identifies a mechanism for the differential expression of gamma c and varied responses to IL-4 by human monocytes compared with MDMac.
Bonder
Claudine S
CS
Department of Microbiology and Infectious Diseases, School of Medicine, Flinders University, Adelaide, GPO Box 2100, Australia 5001.
Davies
Kate V L
KV
Liu
Xiang
X
Hertzog
Paul J
PJ
Woodcock
Joanna M
JM
Finlay-Jones
John J
JJ
Hart
Prue H
PH
D002454:Cell Differentiation; D018920:Coculture Techniques; D006801:Humans; D016898:Interferon-alpha / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D007375:Interleukin-1 / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D009000:Monocytes / Q000166:cytology / Q000378:metabolism*; D012333:RNA, Messenger; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis* / Q000502:physiology; D019948:Receptors, Interleukin-4 / Q000096:biosynthesis* / Q000502:physiology; D050800:STAT6 Transcription Factor; D013582:Synovial Fluid / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism
D016898:Interferon-alpha; D007375:Interleukin-1; D012333:RNA, Messenger; D015375:Receptors, Interleukin-2; D019948:Receptors, Interleukin-4; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; D015534:Trans-Activators; D016753:Interleukin-10; D015847:Interleukin-4