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/lp r mice have a marked defect in endotoxin (LPS)-induced expression of s everal cytokines including interleukin 1 (IL-1). The progressive natur e 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 expressio n 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 c omparison 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 ne arly normal levels. Since an identical defect in IL-1 expression was f ound when MRL/+ m phi were cultured on a variety of extracellular matr ix proteins (including laminin, fibronectin, type I collagen, and type IV collagen), it appears that IL-1 underexpression is dependent on th e 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 adh esion-dependent signaling events necessary to elicit IL-1 underexpress ion are independent of cytoskeletal rearrangement. Taken together, the se results indicate that m phi from autoimmune prone MRL/+ mice have a n adhesion-dependent signaling abnormality that leads to profound unde rexpression of the cytokine IL-1. (C) 1998 Academic Press Limited.