A direct crosstalk between TLR4 and CRH/CRHR pathways links innate immunity with the stress response

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: SUN 389-408-Signaling Originating from Membrane Receptors
Sunday, June 16, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board SUN-399
Thalia Teli*1, Theodora Tzanavari2, Vassilia-Ismini Alexaki3, Triantafyllos Chavakis3, Dimitris Grammatopoulos4 and Katia/Catherine P Karalis5
1Biomedical Research Foundation of the Academy of Athens (BRFAA), Greece, Athens, Greece, 2BRFAA, Athens, Greece, 3Dresden International Graduate School for Biomedicine and Bioengineering, Dresden, Germany, 4Univ of Warwick Biomed Res Inst, Coventry, United Kingdom, 5Biomedical Research Foundation of the Academy of Athens, Athens, Greece
Cross talk between the immune and endocrine system is key in the regulation of innate and adaptive immune response to stressors. In this system the overall response appears to be  orchestrated by the corticotropin-releasing hormone (CRH) which exerts distinct immunomodulatory effects and is supported by glucocorticoids (GC) in maintaining homeostasis.

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 LPS (10μg/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 either LPS or CRH led to a potent, time- dependent phosphorylation of p38MAPK and induction of NF-κB activity. Surprisingly, 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

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: Bhattacharyya S et al., Blood 2007; 109: 4313-4319