Soluble and Cell-Associated Forms of the Adhesion Molecule LFA-3 (CD58) are Differentially Regulated by Inflammatory Cytokines

Abstract

The adhesion molecule lymphocyte function-associated antigen 3 (LFA-3) (CD58) is an important regulator of immune cell function which occurs as both surface-associated and 'soluble' forms. This study has investigated the inter-relationship and the effects of cytokines on the expression of LFA-3 isoforms. The surface antigen was found to be relatively unaffected by cytokines, but the release of soluble LFA-3 (sLFA-3) was highly responsive to interleukin 1/3 (IL-lp), interferon gamma (IFN-y) and tumour necrosis factor alpha (TNF-a). This modulation was cell-specific, particularly with regard to IFN-y, which upregulated sLFA-3 release by A431 cells but down-regulated the release of the soluble form from HEp2 and HepG2 cells. We further demonstrated that LFA-3 is also present in a cytoplasmic 'pool' in each of the cells and, moreover, that cleavage of LFA-3 from the cell surface by phospholipase C resulted in an increase in the levels of the intracellular LFA-3 and replacement of the membrane-associated antigen. These observations suggest that the expression of the surface, soluble and intracellular forms of LFA-3 may be linked by regulatory mechanisms which are likely to exert an important influence on inflammatory interactions.

CD58 Immunobiology at a Glance

“…Thus, different cells exhibit different susceptibility to TNF-α and IFN-γ ( 29 , 56 ). This regulation is cell-specific, especially IFN-γ, which inhibits the release of sCD58 in larynx epidermoid carcinoma cells but promotes the production of the soluble form in lung epidermoid carcinoma cells ( 60 ). In fact, CD58 is also present in a cytoplasmic “pool” of each cell; meanwhile, cleavage of surface CD58 by PLC can result in an increase of intracellular CD58 ( 60 ).…”

“…This regulation is cell-specific, especially IFN-γ, which inhibits the release of sCD58 in larynx epidermoid carcinoma cells but promotes the production of the soluble form in lung epidermoid carcinoma cells ( 60 ). In fact, CD58 is also present in a cytoplasmic “pool” of each cell; meanwhile, cleavage of surface CD58 by PLC can result in an increase of intracellular CD58 ( 60 ). Therefore, the cytoplasmic, membranous, and soluble form of CD58 is likely to be interrelated and dynamic.…”

“…Therefore, the cytoplasmic, membranous, and soluble form of CD58 is likely to be interrelated and dynamic. Apart from the expression level of CD58, activation status, secretory activity, and endogenous protein sheddase levels may be the major reasons for the cell-dependent differences in the production of sCD58 ( 60 ).…”

“…Although alternative splicing, direct secretion, and proteolytic shedding have not yet been corroborated as possible mechanisms of sCD58 production, the sCD58 release is likely to be derived from enzymatic cleavage of membrane-anchored CD58, since lack of a distinct mRNA for sCD58 and the downregulation of CD58 surface expression is always accompanied by the accumulation of sCD58 in the cellular supernatant (58)(59)(60). Furthermore, subsequent studies have revealed that the expression of surface CD58 is decreased following the treatment of PI-specific phospholipase C (PI-PLC) (61).…”