Notch- and Transducin-like Enhancer of Split (TLE)-dependent Histone Deacetylation Explain Interleukin 12 (IL-12) p70 Inhibition by Zymosan

Abstract

IL-12 p70 (1) and IL-23 (2) are cytokines released by antigenpresenting cells that are involved in the induction or amplification of the T-helper type 1 and type 17 responses, respectively. IL-12 p70 and IL-23 share a common chain IL-12 p40 (il12/23b) and differ by another chain, IL-12 p35 (il12a) in the case of IL-12 p70 and IL-12 p19 (il23a) in IL-23. The production of IL-12 p70 and IL-23 is regulated at the transcriptional level and determined by their heterodimeric structure. il12/23b regulation depends on NF-B activation (3), whereas the transcriptional regulation of il12a also requires a type I interferon autocrine-paracrine loop involving interferon regulatory factors (IRF)-1, IRF-3, and IRF-8/ICSBP (3-6). Stimulation of Toll-like receptor (TLR) 3 -4 induces an IL-12/IL-23 balance different from that elicited through the TLR2 and C-type lectin routes (7,8). At first glance, this may be explained because, unlike TLR2, TLR4 ligands activate the MyD88 and the TIR domain-containing adapter-inducing interferon-␤ routes and trigger both the NF-B pathway and the type I IFN autocrine-paracrine loop. However, this does not explain why TLR2 ligands may behave as negative modulators of IL-12 p70 production (7, 9) nor the molecular mechanisms underlying the distinct patterns of IL-23/IL-12 p70 response. Whereas LPS induces both cytokines, Mycobacterium tuberculosis (7) and zymosan, an extract of the cell wall of Saccharomyces cerevisiae mainly composed of ␤-glucans that is recognized by at least the C-type lectin receptor dectin-1 (10) and TLR2 (11, 12), induce IL-23 and a low amount of . Moreover, coligation of the ␤-glucan receptor dectin-1 and TLR2 enhances IL-23 and down-regulates IL-12 p70, but there is no mechanistic explanation for this finding (8,16). Addressing whether the effect of zymosan occurs via inhibition of il12a transcription or through a sole stimulation of il23a transactivation has pathophysiological relevance, because IL-23 takes part in the defense against pathogens and in the development of autoimmunity. Several hypotheses can be put forward to explain the distinct IL-12/ IL-23 balances elicited by different stimuli as follows. (i) il23a induction could be explained through the activation of transcription factors of the family ATF-2/CREB. In fact, competition between CRE-binding protein (CREB) and NF-B for the coactivator CREB-binding protein (CBP) explains the IL-12 p70 ϩ/Ϫ /IL-10 ϩϩϩ pattern induced by zymosan in dendritic cells (DC) (17). A corollary to this finding is that stimuli with a

Fungal pattern receptors down‐regulate the inflammatory response by a cross‐inhibitory mechanism independent of interleukin‐10 production

“…b). In keeping with previous reports, zymosan was a weak stimulus of Il12a mRNA expression and a strong inducer of Il23a and Ifnb1 mRNA (Fig. b).…”

Increased cAMP in Monocytes Augments Notch Signaling Mechanisms by Elevating RBP-J and Transducin-like Enhancer of Split (TLE)

“…In addition to activating the Notch signaling pathway, cAMP is able to increase levels of TLE, which is a transcriptional corepressor recruited to gene promoters by DNA binding proteins such as Hes (19 -21, 26). The transcription repressor complex resulting from TLE and Hes1 is important for mediating many of the Notch signaling effects and was observed recently to play a role in the ability of zymosan to suppress IL-12 production in dendritic cells (27). Results from these studies indicate that cAMP induces the formation of the TLE/Hes1 complex, which likely results from the ability of cAMP to activate the Notch pathway and increase levels of TLE.…”

The Response of Human Macrophages to β-Glucans Depends on the Inflammatory Milieu

“…This pattern of cooperation differs from other systems where CREB and RelA/p65 bind to different promoters and may compete for the coactivator CBP [37]. The predominant production of IL-23 could be explained by the ability of zymosan to blunt il12a transcription [38].…”