Critical Roles of Myeloid Differentiation Factor 88-Dependent Proinflammatory Cytokine Release in Early Phase Clearance ofListeria monocytogenesin Mice

Abstract

Listeria monocytogenes (LM), a facultative intracellular Gram-positive bacterium, often causes lethal infection of the host. In this study we investigated the molecular mechanism underlying LM eradication in the early phase of infection. Upon infection with LM, both IL-12 and IL-18 were produced, and then they synergistically induced IFN-γ production, leading to normal LM clearance in the host. IFN-γ knockout (KO) mice were highly susceptible to LM infection. IL-12/IL-18 double knockout mice were also highly susceptible. Their susceptibility was less than that of IFN-γ KO mice, but more than that of single IL-12 or IL-18 KO mice. Mice deficient in myeloid differentiation factor 88 (MyD88), an essential adaptor molecule used by signal transduction pathways of all members of the Toll-like receptor (TLR) family, showed an inability to produce IL-12 and IFN-γ following LM infection and were most susceptible to LM. Furthermore, MyD88-deficient, but not IFN-γ-deficient, Kupffer cells could not produce TNF-α in response to LM in vitro, indicating the importance of MyD88-dependent TNF-α production for host defense. As TLR2 KO, but not TLR4 KO, mice showed partial impairment in their capacity to produce IL-12, IFN-γ, and TNF-α, TLR2 activation partly contributed to the induction of IL-12-mediated IFN-γ production. These results indicated a critical role for TLRs/MyD88-dependent IL-12/TNF-α production and for IL-12- and IL-18-mediated IFN-γ production in early phase clearance of LM.

Cutting Edge: Protective Cell-Mediated Immunity to Listeria monocytogenes in the Absence of Myeloid Differentiation Factor 88

“…The increased susceptibility of MyD88-deficient mice to primary infection with wt LM has been recently described (7,8), and our initial experiments confirmed these findings (data not shown). By contrast, MyD88-deficient mice were resistant to infection with a mutant strain of LM deficient in intracellular motility as a result of targeted deletion in the actA gene (15).…”

Innate and adaptive immune responses to Listeria monocytogenes: a short overview

“…The most important TLR for L. monocytogenes recognition appears to be TLR2. TLR2-deficient macrophages after in vitro infection with L. monocytogenes secrete less TNFα, IFNγ, IL-1β and IL-12 [39][40][41]. However, mice deficient in TLR2 have little increase in bacterial burden compared to wild-type mice [40].…”

“…Binding of the TLR ligand to its appropriate receptor initiates a signaling cascade that results in activation of the transcription factor NF-κB resulting in expression of different cytokine and antigen presentation related genes. Mice deficient in the key adaptor molecule, MyD88, which is important for signaling from several TLRs, are highly susceptible to L. monocytogenes infection [39,40].…”

Myeloid Differentiation Antigen 88 Deficiency Impairs Pathogen Clearance but Does Not Alter Inflammation inBorrelia burgdorferi-Infected Mice

“…Immunization with ovalbumin in alum can elicit Th2 responses, indicating that priming for Th2 responses is intact. MyD88 Ϫ/Ϫ mice exhibit an increased susceptibility to infections with intracellular pathogens, due in part to a deficiency in IL-12 production by dendritic cells (34,37). MyD88 Ϫ/Ϫ mice also exhibit early lethality after infection with gram-positive organisms such as Staphylococcus aureus, which are recognized preferentially by TLR2, and to a lesser extent, by other TLRs (38).…”