CaMK4-dependent activation of AKT/mTOR and CREM-α underlies autoimmunity-associated Th17 imbalance
Tomohiro Koga, … , José C. Crispín, George C. Tsokos
Tomohiro Koga, … , José C. Crispín, George C. Tsokos
Published March 25, 2014
Citation Information: J Clin Invest. 2014;124(5):2234-2245. https://doi.org/10.1172/JCI73411.
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Research Article Immunology

CaMK4-dependent activation of AKT/mTOR and CREM-α underlies autoimmunity-associated Th17 imbalance

Abstract

Tissue inflammation in several autoimmune diseases, including SLE and MS, has been linked to an imbalance of IL-17–producing Th (Th17) cells and Tregs; however, the factors that promote Th17-driven autoimmunity are unclear. Here, we present evidence that the calcium/calmodulin-dependent protein kinase IV (CaMK4) is increased and required during Th17 cell differentiation. Isolation of naive T cells from a murine model of lupus revealed increased levels of CaMK4 following stimulation with Th17-inducing cytokines but not following Treg, Th1, or Th2 induction. Furthermore, naive T cells from mice lacking CaMK4 did not produce IL-17. Genetic or pharmacologic inhibition of CaMK4 decreased the frequency of IL-17–producing T cells and ameliorated EAE and lupus-like disease in murine models. Inhibition of CaMK4 reduced Il17 transcription through decreased activation of the cAMP response element modulator α (CREM-α) and reduced activation of the AKT/mTOR pathway, which is known to enhance Th17 differentiation. Importantly, silencing CaMK4 in T cells from patients with SLE and healthy individuals inhibited Th17 differentiation through reduction of IL17A and IL17F mRNA. Collectively, our results suggest that CaMK4 inhibition has potential as a therapeutic strategy for Th17-driven autoimmune diseases.

Authors

Tomohiro Koga, Christian M. Hedrich, Masayuki Mizui, Nobuya Yoshida, Kotaro Otomo, Linda A. Lieberman, Thomas Rauen, José C. Crispín, George C. Tsokos

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Figure 1

CaMK4 is induced during Th17 differentiation.

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CaMK4 is induced during Th17 differentiation. (A) Western blot analysis ...
(A) Western blot analysis of CaMK4 and phospho-STAT3 in unstimulated (UN) cells from MRL/lpr mice and cells stimulated under Th0, Th17, and Treg conditions. Cumulative data of densitometry is also shown (*P < 0.05; mean ± SEM; n = 3). (B) Real-time PCR analysis of Camk4 mRNA in naive CD4+ T cells from MRL/lpr mice stimulated 6 hours in Th0-, Th1-, Th2-, Th17-, or Treg-polarizing conditions. Results were normalized to Gapdh (*P < 0.05; mean ± SEM; n = 4). (C) Expression of Camk1, Camk2d, Camk2g, and Camk4 mRNA in naive CD4+ T cells at different time points during Th0 or Th17 differentiation (*P < 0.05; mean ± SEM; n = 4–5). Data are representative of 3 independent experiments.