Activation of Murine Peritoneal Macrophages with Cisplatin and Lipopolysaccharide: Involvement of Protein Kinase C and Tyrosine Kinase.

Abstract

SummaryIn the present study we report that protein kinase C (PKC) inhibitors, H-7 and chelerythrine chloride, inhibit the cisplatin-or lipopolysaccharide (LPS)-induced activation of murine peritoneal macrophages to the tumoricidal state. Similarly, the tumoricidal activity was also downregulated by protein tyrosine kinase (PTK) inhibitors, genestein and lavendustin A. The production of interleukin-1 (IL-1) and tumor necrosis factor (TNF) by cisplatin-or LPS-treated macrophages was also inhibited by both PKC and PTK inhibitors.These findings suggest the involvement of PKC and PTK in the activation of murine peritoneal macrophages with cisplatin and LPS.Key Words: macrophage, PKC, PTK, IL-1, TNF The development of macrophage host defense functions (eg., antimicrobial or tumoricidal activities) is mediated by a variety of agents ranging from several cytokines [1-4] to bacterial products [5,6] and various chemotherapeutic drugs [7][8][9]. Cisplatin [cis-dichlorodiamine platinum (II)], a potent antitumor compound, has been used successfully against a number of tumors in animals and human cancers [10][11][12]. This compound has been reported to activate murine peritoneal and bone marrow-derived macrophages to the tumoricidal state [13][14][15], in which state the cells show increased production of interleukin-1 (IL-1) and tumor necrosis factor (TN F) [16], reactive oxygen metabolites [17,18], reactive nitrogen intermediates [19], lysozyme, and arginase [20].It has been demonstrated that the binding of LPS or IFN-y to cell-surface receptors initiates a cascade of events involving membrane phosphoinositidederived second messengers, Cat, cyclic nucleotides, PKC, and PTK [21,22]. New lines of evidence support the hypothesis that a component of cisplatin uptake is an active carrier-mediated mechanism [23]. Our recent studies have shown that

In VitroActivation of Murine Peritoneal Macrophages by Monocyte Chemoattractant Protein-1: Upregulation of CD11b, Production of Proinflammatory Cytokines, and the Signal Transduction Pathway

“…Supporting this, the role of PKC and tyrosine kinases in macrophage TNF-a and IL-1 production was reported earlier from our laboratory. (55) Inhibition of both these responses in the presence of genistein for MCP-1-treated macrophages also suggests the participation of protein tyrosine kinases. Activation of nonreceptor tyrosine kinases such as src, syk, and pyk2H, was reported for other CC chemokines, that is, macrophage inflammatory protein-1a (MIP-1a), MIP-1b, and RANTES.…”

Signaling molecules involved in production and regulation of IL-1β by murine peritoneal macrophages in vitro on treatment with Concanavalin A

“…The receptor on cell surface after ligand binding triggers a cascade of events involving protein phosphorylation, calcium flux and generation of membrane inositol derived secondary messenger culminating in the transcription of proinflammatory genes like IL-1β and TNF-α [43][44][45][46][47][48]. Protein phosphorylation mediated by tyrosine kinase and serine/threonine kinase have been correlated with the production of TNF-α and other cytokines in macrophages activated by agent such as LPS, interleukins and the anticancer drug cisplatin [20,48].…”

Production of TNF-α, IL-1β, IL-12 and IFN-γ in murine peritoneal macrophages on treatment with wheat germ agglutinin in vitro: involvement of tyrosine kinase pathways

“…The receptor on cell surface after ligand binding triggers a cascade of events involving protein phosphorylation, calcium flux and generation of membrane inositol derived secondary messenger culminating in the transcription of proinflammatory cytokine genes like IL-1b and TNF-a [36][37][38][39][40][41]. Protein phosphorylation mediated by tyrosine kinase and serine/threonine kinases have been correlated with the production of TNF-a and other cytokines in macrophages activated by agents such as LPS, interleukins and the anticancer drug cisplatin [3,41].…”