Session: SUN 389-408-Signaling Originating from Membrane Receptors
Poster Board SUN-399
In our previous work, CRH was shown to exert transcriptional regulation of Toll-like receptor (TLR)-4 in the colon of mice with severe inflammatory colitis, highlighting the integration of the two systems. In the present study we sought to investigate whether direct interaction between components of the CRH and the TLR4 signaling cascades is important in shaping overall inflammatory responses.
In vitro studies with regards to the role of CRH on macrophage polarization in RAW264.7 mouse macrophages and peritoneal macrophages from male wild type C57BL/6 mice were performed. CRH alone or together with LPS stimulated IL-12b and IL-6 expression. On the other hand, CRH decreased the IL-4-stimulated macrophage expression of IL-10, Arg1 and Ym1.
Further studies in RAW264.7 mouse macrophages were carried out to elucidate interaction of CRH to TLR4 signaling. Co-immunoprecipitation and confocal microscopy experiments suggested a direct cross-talk between the CRH-R and TLR4 signaling, since simultaneous activation of the two receptors with LPS10μg/ml) and CRH (100nM) reveals co-localization of TNF receptor-associated factor 6 (TRAF6), a significant component of the TLR4 signaling, with the Gβγ-proteins.
Moreover, treatment of RAW macrophages with eitherLPS or CRH led to a potent, time- dependent phosphorylation of p38MAPK and induction of NF-κB activitySurprisingly, simultaneous activation of the CRH and the TLR4 pathways resulted in suppression of p38MAPK and JNK activation, via a mechanism involving up-regulation of the specific MAPK phosphatase 1 (MKP-1). In addition to direct effects of local CRH actions, GCs exert similar effects on p38MAPK and MKP-1 regulation suggesting utilization of common pathways operating at different levels to attenuate proinflammatory responses in macrophages (1).
We propose that targeting CRH and enhancing its above actions may provide new ways to control innate immune responses and support resolution of local and systemic inflammation.
Nothing to Disclose: TT, TT, VIA, TC, DG, KPK
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