In vitro and in vivo macrophage function can occur independently of SLP-76.
Expression of SH2 domain-containing leukocyte-specific phosphoprotein of 76 kDa (SLP-76), a hematopoietic cell-specific adapter protein, is required to couple Syk family tyrosine kinase activation to downstream mediators such as phospholipase C (PLC)-gamma following TCR, platelet collagen receptor and mast cell Fc epsilon R stimulation. In addition to T cells, mast cells and platelets, SLP-76 is expressed in monocytes and macrophages. To determine the role of SLP-76 in Fc gamma R-stimulated signaling pathways in macrophages, we examined cultured bone marrow-derived macrophages (BMM) from SLP-76(-/-) and wild-type mice. In this study, we show that Fc gamma R cross-linking rapidly induces tyrosine phosphorylation of SLP-76 in wild-type BMM. Surprisingly, however, BMM from SLP-76(-/-) mice activate ERK2 and phosphorylate PLC-gamma 2 following Fc gamma R ligation. Furthermore, SLP-76(-/-) BMM display normal Fc gamma R-dependent phagocytic function and reactive oxygen intermediate production. SLP-76(-/-) and SLP-76(+/+) BMM secrete comparable levels of IL-12 in response to lipopolysaccharide and IFN-gamma. To examine macrophage function in vivo, SLP-76(-/-) mice were challenged i.v. with Listeria monocytogenes. SLP-76(-/-) mice survive and efficiently contain the acute phase of infection similar to wild-type mice but exhibit a stable chronic infection attributed to the lack of mature T cells. These data show that, although SLP-76 is required to couple Syk family PTK activity to downstream mediators and effector functions in Fc gamma R-induced pathways in some cell types, activation of Fc gamma R-dependent pathways occurs independently of SLP-76 in BM
Myung
P S
PS
Department of Physiology and Biophysics, University of Iowa College of Medicine and Veterans Administration Medical Center, Iowa City 52242, USA.
Clements
J L
JL
White
D W
DW
Malik
Z A
ZA
Cowdery
J S
JS
Allen
L H
LH
Harty
J T
JT
Kusner
D J
DJ
Koretzky
G A
GA
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D018664:Interleukin-12 / Q000096:biosynthesis; D008088:Listeriosis / Q000401:mortality; D008264:Macrophages / Q000502:physiology*; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000502:physiology; D010587:Phagocytosis; D010750:Phosphoproteins / Q000502:physiology; D010766:Phosphorylation; D017382:Reactive Oxygen Species; D017452:Receptors, IgG / Q000502:physiology; D012756:Sheep; D010738:Type C Phospholipases / Q000502:physiology; D014443:Tyrosine / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D010750:Phosphoproteins; D017382:Reactive Oxygen Species; D017452:Receptors, IgG; C092947:SLP-76 signal Transducing adaptor proteins; D018664:Interleukin-12; D014443:Tyrosine; D019950:Mitogen-Activated Protein Kinase 1; D010738:Type C Phospholipases