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  • Since PTKs are involved in numerous aspects of cell function


    Since PTKs are involved in numerous aspects of cell function, their regulation is critical for cell survival and function. The carboxyl-terminal tyrosine of Src-family PTKs is a key site of regulation. Phosphorylation on this carboxyl-terminal tyrosine contributes to the induction of a conformational change in the PTKs, resulting in suppression of their catalytic activity (Thomas and Brugge, 1997). The cytoplasmic protein-tyrosine kinase (Csk) was initially identified as the only PTK capable of phosphorylating c-Src on the carboxy-terminal regulatory tyrosine residue (Nada et al., 1991, Okada and Nakagawa, 1989, Cooper et al., 1986). However, we and others have recently cloned a Csk homologous kinase (Chk) (Grgurevich et al., 1997, McVicar et al., 1994, Sakano et al., 1994, Bennett et al., 1994). Chk is present in two isoforms, p57Chk and p52Chk (Chow et al., 1994a), and it appears that in human monocytes and human T cells, the p57Chk isoform is predominant (McVicar et al., 1994, Musso et al., 1994). Like Csk, Chk phosphorylates the negative regulatory tyrosine residue of the Src family kinases, suggesting that Chk shares at least some functional properties with Csk (Davidson et al., 1997). The restricted pattern of expression of Chk to neurons and hematopoetic transferases (Chow et al., 1994b, Musso et al., 1994, Avraham et al., 1995), in comparison with the ubiquitous expression of Csk (Nada et al., 1991), implies that Chk may play a highly specific role in regulating Src-family kinases within immune cells. Monocytes participate both in the initiation and maintenance of the immune response by virtue of their ability to respond in a timely fashion to various soluble factors. These responses are mediated, at least in part, by lymphokines secreted by the different subsets of T helper cells and by the ability of macrophages to respond to cytokines (Gordon, 1999). Sensitized T helper cells can be divided into two major subsets, Th1 and Th2, based on their distinct cytokine profiles (Mosmann and Sad, 1996). Th1 cells secrete predominantly IL-2, IFN-γ and lymphotoxin, while Th2 cells produce IL-4, IL-5, IL-10 and IL-13 (Mosmann and Sad, 1996). There is considerable evidence to indicate that Th1 and Th2 cell products have opposite effects on monocyte functions, in particular, on the production of IL-1, TNF-α, IL-6, and PGE-2 (Donnelly et al., 1990, Essner et al., 1989, Hart et al., 1989, Cheung et al., 1990, Chizzolini et al., 1997, Endo et al., 1998, Berger et al., 1996). We have previously reported that Chk expression in monocytes is induced by the Th2 cytokines, IL-4 and IL-13, and blocked by co-culture with IFN-γ (Musso et al., 1994). The ability of the Th2 cytokines, IL-4 and IL-13, to suppress many monocytic functions (Donnelly et al., 1990, Essner et al., 1989, Hart et al., 1989, Cheung et al., 1990) while inducing Chk expression (Musso et al., 1994) suggests a negative regulatory function for Chk. In addition, the lack of Chk expression following stimulation with IFN-γ (Musso et al., 1994), a Th1 product and a potent activator of monocytes, suggests a prerequisite suppression of Chk expression during productive macrophage/monocyte activation or differentiation. Despite the potential significance of Chk induction, the roles of other members of the IL-4 family of lymphokines, IL-3, IL-5, and GM-CSF (Boulay and Paul, 1992), on the induction of Chk in monocytes have not been addressed. Lymphokines in the IL-4 family appear to be involved in monocytic differentiation. For example, GM-CSF and IL-4 have been extensively shown to have an effect on monocyte differentiation. In human T- and B-cell-depleted blood cells, GM-CSF stimulation results in the differentiation of this population to macrophages (Romani et al., 1994). However, addition of both GM-CSF and IL-4 to myeloid precursors induces their differentiation into dendritic cells (Romani et al., 1994, Sallusto and Lanzavecchia, 1994). In this system, GM-CSF induces aggregates of dendritic cell precursors (Romani et al., 1994) while IL-4 inhibits macrophage colony formation (Jansen et al., 1989). It can be hypothesized that myeloid precursors differentiate into macrophages following GM-CSF stimulation in the absence of an IL-4 signal which suppresses the differentiation (Jonuleit et al., 1996). These examples demonstrate the significance of IL-4 family signaling in the differentiation of macrophages and dendritic cells. Because of the role the IL-4 family appears to have on monocyte differentiation, we have chosen to address the effect of these cytokines on Chk expression in monocytes. Regulation of Chk in monocytes by the IL-4 family of cytokines may suggest a role for Chk in mediating the signals necessary for macrophage/dendritic cell differentiation.