DIFFERENTIAL REGULATION OF CYTOKINE AND CYTOKINE RECEPTOR MESSENGER-RNA EXPRESSION UPON INFECTION OF BONE-MARROW-DERIVED MACROPHAGES WITH LISTERIA-MONOCYTOGENES

Cytokine and cytokine receptor mRNA expression was analyzed by PCR-ass isted amplification of RNA extracted from bone marrow-derived macropha ges (BMM phi) at different time points after infection with Listeria m onocytogenes, The mRNAs for the cytokines interleukin-1 alpha (IL-1 al pha), IL-1 beta, and tumor necrosis factor alpha (TNF-alpha) were indu ced early after infection, whereas IL-6 mRNA appeared later and even n onhemolytic Listeria strains, which are unable to grow inside eukaryot ic cells, induced the same cytokine mRNAs at levels similar to those o f the wild-type strain. In most cases, the amounts of cytokines determ ined by various bioassays correlated with the level of mRNA induction, Inhibition of phagocytic uptake of L. monocytogenes by cytochalasin D treatment resulted in adherent bacteria which still induced the proin flammatory cytokines, In BMM phi, the level of IL-1 receptor II mRNA w as unaffected, whereas mRNA expression of the two subtypes of tumor ne crosis factor receptors (TNF-RI and TNF-RII) was differentially regula ted upon infection: transcription of TNF-RI was reduced, and that of T NF-RII mRNA was induced, Similar to the decreased TNF-RI mRNA expressi on, gamma interferon receptor mRNA was downregulated in L. monocytogen es-infected BMM phi. This dose- and time-dependent induction or downre gulation of cytokine receptor mRNA following L. monocytogenes infectio n of BMM phi was not observed upon infection of established macrophage like cell lines J774 and P388D(1), Induction of IL-6 mRNA as well as IL-1 alpha/beta and TNF-alpha mRNAs upon L. monocytogenes infection of BMM phi occurs independently of autocrine TNF-alpha signaling via TNF -RI or TNF-RII, as shown by infection of TNF-RI- and TNF-RII-deficient macrophages derived from mutant B6x129 mice, In contrast to gamma int erferon receptor mRNA, both TNF receptor subtype mRNAs were not influe nced by L. monocytogenes infection of hybrid (B6x129) mouse macrophage s. Whereas the proinflammatory cytokine mRNAs were even induced after infection with the nonpathogenic species L. innocua, no alteration of cytokine receptor mRNA expression was observed after challenge of BMM phi with this nonpathogenic species, suggesting that the modulation of cytokine and cytokine receptor expression by L. monocytogenes could b e an important way of inhibition of macrophage stimulation.