genomewide characterization of host-pathogen interactions by ...

Maren Depke
Discussion and Conclusions
superfamilies of TNF ligands and receptors were identified (Hehlgans/Pfeffer 2005). TNF is
associated with several functions linked to pro-inflammatory effects, which involve a
multiprotein signaling complex at the cell membrane and MAP-kinase signaling and which are
finally mediated via NFκB and c-Jun (Chen G/Goeddel 2002, Wajant et al. 2003). Rarely, TNF can
induce apoptosis via caspase activation, depending on the cellular balance of antiapoptosis/proliferation
signals mediated by NFκB (Gaur/Aggarwal 2003, Wajant et al. 2003).
Furthermore, TNF is involved in the regulation of fever with both pyrogenic and antipyretic
effects depending on physiological or experimental conditions (Leon 2002). In macrophages, TNF
has an important function in controlling intracellular mycobacterial growth (Bekker et al. 2001).
TNF deficient mice are susceptible to Listeria monocytogenes infections, exhibit reduced contact
hypersensitivity and impairment of splenic follicular architecture and of maturation of the
humoral immune response (Pasparakis et al. 1996). Knockout of TNF and lymphotoxin-α (TNF-β)
leads to an increased susceptibility to S. aureus infections, but also to a reduced frequency of
arthritis indicating a damaging influence of the cytokine during the inflammatory reaction
(Hultgren et al. 1998). Reflecting the central position of TNF in the regulation of the immune
response to infection, several strategies of pathogens to influence the TNF activity were
reported. The interference can lead to diverse and contrary effects depending on the pathogen,
like inhibition of apoptosis, enhancement of apoptosis, inhibition of TNF production or, in case of
S. aureus, the induction of a TNF-like response by interaction of protein A with the TNF receptor
TNFR1 (Rahman/McFadden 2006).
Beside other functions, TNF was described to further enhance the expression of the
immunoproteasome (Loukissa et al. 2000). In non-professional antigen-presenting cells, the
induction of immunoproteasome, TAP peptide transporters, and MHC class I complexes by TNF
independent of IFN-γ activity was observed and in addition increased stability of the MHC class I
complexes at the cell surfaces (Hallermalm et al. 2001). Thus, induction of TNF in BMM after
IFN-γ treatment might intensify the effect on antigen processing and presentation after a second
stimulus. Also in the serum-free system, the inducibility of TNF in IFN-γ and LPS treated BMM was
described (Eske et al. 2009). IL-6, IL-10, and IL-12, which were also inducible by IFN-γ and LPS
(Eske et al. 2009), were not expressed in IFN-γ treated BMM (this study), and the IFN-γ and LPS
inducible chemokine Ccl2 (MCP-1; Eske et al. 2009) was expressed but not differentially regulated
in IFN-γ treated BMM (this study). This strongly hints for the explanation that the induction only
occurs when a second stimulus like LPS is given.
After IFN-γ treatment, the induction of anti-inflammatory IL-10 receptor (Moore et al. 2001)
as well as the induction of Il18bp coding for an IL-18 binding protein, which is a natural
endogenous inhibitor of the proinflammatory IL-18 (McInnes et al. 2000, Gracie et al. 2003,
Novick D et al. 1999), was observed (this study). Not only Stat1 and Irf1 of the positive IFN-γ
feedback were induced, but also Stat3 and Socs1 which are implicated in negative feedback
(Schroder et al. 2004, Hu et al. 2008). This might indicate the possible reactivity to antiinflammatory
stimuli and a confinement of inflammatory response.
After the priming signal of IFN-γ, the BMM are not fully activated and are not expected to
secrete cytokines, but rather after a second stimulus (Hu et al. 2008). Analysis of cytokine
secretion of BMM beyond the examples analyzed until now will be of interest, either after
stimulation with LPS, or after stimulation with molecules of Gram-positive bacteria or even
infection e. g. with S. aureus, as it will be in focus of research for follow-up experiments to this
study.
185