Adhesion elicits an intrinsic defect in interleukin-1 expression by macrophages from autoimmune-prone MRL mice.
Macrophages (m phi) from prediseased autoimmune-prone MRL/+ and MRL/ lpr mice have a marked defect in endotoxin (LPS)-induced expression of several cytokines including interleukin 1 (IL-1). The progressive nature of this defect over time suggests that it may develop in response to specific extracellular stimuli. In this report, we show that adhesion is an essential factor for the development of aberrant IL-1 expression by m phi from autoimmune-prone MRL mice. Thus, when MRL/+ m phi were allowed to adhere before being stimulated with LPS, they demonstrated a striking defect in expression of both IL-1 message and protein in comparison with multiple normal strains. In marked contrast, when MRL/+ m phi were maintained in a non-adherent state by culture on agarose, the IL-1 defect was not evident and IL-1 expression was restored to nearly normal levels. Since an identical defect in IL-1 expression was found when MRL/+ m phi were cultured on a variety of extracellular matrix proteins (including laminin, fibronectin, type I collagen, and type IV collagen), it appears that IL-1 underexpression is dependent on the adhesive state per se rather than on engagement of any one specific adhesion receptor. Moreover, the cytoskeletal inhibitor cytochalasin D had no effect on the magnitude of the defect, indicating that the adhesion-dependent signaling events necessary to elicit IL-1 underexpression are independent of cytoskeletal rearrangement. Taken together, these results indicate that m phi from autoimmune prone MRL/+ mice have an adhesion-dependent signaling abnormality that leads to profound underexpression of the cytokine IL-1.
Levine
J S
JS
Renal Section, Boston Medical Center, Massachusetts 02118, USA. jlevine@bu.edu
Koh
J S
JS
Hartwell
D
D
Beller
D I
DI
D000818:Animals; D001327:Autoimmune Diseases / Q000473:pathology*; D002448:Cell Adhesion; D002478:Cells, Cultured; D003470:Culture Media; D003571:Cytochalasin B / Q000494:pharmacology; D003599:Cytoskeleton / Q000187:drug effects / Q000502:physiology; D004198:Disease Susceptibility; D016326:Extracellular Matrix Proteins; D005786:Gene Expression Regulation; D006579:Heterozygote; D007375:Interleukin-1 / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D008232:Lymphoproliferative Disorders / Q000473:pathology*; D017737:Macrophages, Peritoneal / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D019463:Mice, Inbred MRL lpr; D008815:Mice, Inbred Strains; D012685:Sepharose; D015398:Signal Transduction
D003470:Culture Media; D016326:Extracellular Matrix Proteins; D007375:Interleukin-1; D008070:Lipopolysaccharides; D003571:Cytochalasin B; D012685:Sepharose