Dendritic cells (DC) are the most potent APCs known that play a key role for the initiation of immune responses. Ag presentation to T lymphocytes is likely a constitutive function of DC that continues during the steady state. This raises the question of which mechanism(s) determines whether the final outcome of Ag presentation will be induction of immunity or of tolerance. In this regard, the mechanisms controlling DC immunogenicity still remain largely uncharacterized. In this paper we report that the nuclear receptor peroxisome proliferator-activated receptor γ (PPAR-γ), which has anti-inflammatory properties, redirects DC toward a less stimulatory mode. We show that activation of PPAR-γ during DC differentiation profoundly affects the expression of costimulatory molecules and of the DC hallmarker CD1a. PPAR-γ activation in DC resulted in a reduced capacity to activate lymphocyte proliferation and to prime Ag-specific CTL responses. This effect might depend on the decreased expression of costimulatory molecules and on the impaired cytokine secretion, but not on increased IL-10 production, because this was reduced by PPAR-γ activators. Moreover, activation of PPAR-γ in DC inhibited the expression of EBI1 ligand chemokine and CCR7, both playing a pivotal role for DC migration to the lymph nodes. These effects were accompanied by down-regulation of LPS-induced nuclear localized RelB protein, which was shown to be important for DC differentiation and function. Our results suggest a novel regulatory pathway for DC function that could contribute to the regulated balance between immunity induction and self-tolerance maintenance.
Ligands of the prototypical activating NK receptor NKG2D render cancer cells susceptible to NK cell-mediated cytolysis if expressed at sufficiently high levels. However, malignant cells employ mechanisms to evade NKG2D-mediated immunosurveillance, such as NKG2D ligand (NKG2DL) shedding resulting in reduced surface expression levels. In addition, systemic downregulation of NKG2D on NK cells of cancer patients has been observed in many studies and was attributed to soluble NKG2DL (sNKG2DL), although there also are conflicting data. Likewise, relevant expression of NKG2DL in leukemia has been reported by some, but not all studies. Hence, we comprehensively studied expression, release, and function of the NKG2D ligands MHC class I chain-related molecules A and B and UL16-binding proteins 1–3 in 205 leukemia patients. Leukemia cells of most patients (75%) expressed at least one NKG2DL at the surface, and all investigated patient sera contained elevated sNKG2DL levels. Besides correlating NKG2DL levels with clinical data and outcome, we demonstrate that sNKG2DL in patient sera reduce NKG2D expression on NK cells, resulting in impaired antileukemia reactivity, which also critically depends on number and levels of surface-expressed NKG2DL. Together, we provide comprehensive data on the relevance of NKG2D/NKG2DL expression, release, and function for NK reactivity in leukemia, which exemplifies the mechanisms underlying NKG2D-mediated tumor immunosurveillance and escape.
Proteasome inhibitors are emerging as effective drugs for the treatment of multiple myeloma and possibly certain subtypes of non-Hodgkin's lymphoma. Bortezomib (Velcade) is the first proteasome inhibitor proven to be clinically useful and will soon be followed by a second generation of small molecule inhibitors with improved pharmacological properties. Although it is now understood that certain types of malignancies have an exquisite dependence on a functional proteasome for their survival, the underlying reason(s) remain unclear as of now. In this context, addiction to nuclear factor-jB (NF-jB)-induced survival signals, activation of the unfolded protein response as well as a reduced proteasomal activity in differentiated plasma cells have all been proposed to justify proteasome inhibitors' activity in susceptible tissues. The ubiquitin-proteasome pathway and its relevance to cancerThe ubiquitin-proteasome pathway (UPP) mediates the degradation of polyubiquitinated proteins and represents the main protein degradation pathway in eucaryotic cells. 1 It is estimated that more than 80% of intracellular proteins are degraded by the proteasome. Besides carrying out protein turnover, the UPP plays an essential role in regulating protein levels during cell cycle, apoptosis, response to cellular stress (i.e. DNA damage, hypoxia) and intracellular signal transduction, not to mention its importance for the generation of antigenic epitopes to be presented on human leukocyte antigen (HLA) molecules. It is now known that some types of cancer are exquisitely prone to undergo apoptosis in response to inhibition of the UPP pathway, a phenomenon that, at present, still lacks a precise explanation. 2,3 Intracellular proteins are targeted for degradation by the conjugation of polyubiquitin chains to lysine residues of the protein, a process carried out by ubiquitin-conjugating enzymes and antagonized by deubiquitinating proteases (revised by Nijman et al. 4 ). 1 Ubiquitination is performed by three enzymes: a ubiquitin-activating enzyme (E1), a ubiquitin-conjugating enzyme (E2) and a ubiquitin ligase (E3). E1 activates ubiquitin monomers by adenylation and transfers them to E2, which in turn works in conjunction with E3 to confer substrate specificity. Whereas E1 only exists in two isoforms derived from alternative splicing of the same messenger at least 25 E2 and hundreds of E3 enzymes exist. 1 A similar complexity is shared by the deubiquitinating enzymes, of which more than 500 are represented in the human genome, thus indicating the high complexity and specificity of this regulatory mechanism. 4 The proteasome is an enzymatic complex that recognizes ubiquitin-tagged proteins and catalyses their proteolytic degradation in an ATP-dependent fashion. 1-3 Proteasomes can be found both in the cytoplasm and in the nucleus of eucaryotic cells. The proteasome typically consists of a 20S component, which is normally associated to a 19S or to an 11S (inducible by interferon-g) regulator component. The 20S proteasome component is compris...
Dendritic cells (DCs) play an important role in initiating and maintaining primary immune responses. However, mechanisms involved in the resolution of these responses are elusive. We analyzed the effects of 15d-PGJ2 and the synthetic peroxisome proliferator-activated receptor (PPAR)-gamma ligand troglitazone (TGZ) on the immunogenicity of human monocyte-derived DCs upon stimulation with toll-like receptor (TLR) ligands. Activation of PPAR-gamma resulted in a reduced stimulation of DCs via the TLR ligands 2, 3, 4, and 7, characterized by down-regulation of costimulatory and adhesion molecules and reduced secretion of cytokines and chemokines involved in T-lymphocyte activation and recruitment. MCP-1 (monocyte chemotactic protein-1) production was increased due to PPAR-gamma activation. Furthermore, TGZ-treated DCs showed a significantly reduced capacity to stimulate T-cell proliferation, emphasizing the inhibitory effect of PPAR-gamma activation on TLR-induced DC maturation. Western blot analyses revealed that these inhibitory effects on TLR-induced DC activation were mediated via inhibition of the NF-kappaB and mitogen-activated protein (MAP) kinase pathways while not affecting the PI3 kinase/Akt signaling. Our data demonstrate that inhibition of the MAP kinase and NF-kappaB pathways is critically involved in the regulation of TLR and PPAR-gamma-mediated signaling in DCs.
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