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.
Publication types
-
Clinical Trial
-
Research Support, N.I.H., Extramural
MeSH terms
-
Animals
-
Calcium-Calmodulin-Dependent Protein Kinase Type 4 / genetics
-
Calcium-Calmodulin-Dependent Protein Kinase Type 4 / immunology*
-
Cell Differentiation / genetics
-
Cell Differentiation / immunology
-
Cyclic AMP Response Element Modulator / genetics
-
Cyclic AMP Response Element Modulator / immunology*
-
Enzyme Activation / genetics
-
Enzyme Activation / immunology
-
Female
-
Humans
-
Interleukin-17 / genetics
-
Interleukin-17 / immunology
-
Lupus Erythematosus, Systemic / genetics
-
Lupus Erythematosus, Systemic / immunology*
-
Lupus Erythematosus, Systemic / pathology
-
Lupus Erythematosus, Systemic / therapy
-
Male
-
Mice
-
Mice, Knockout
-
Multiple Sclerosis / genetics
-
Multiple Sclerosis / immunology*
-
Multiple Sclerosis / pathology
-
Multiple Sclerosis / therapy
-
Proto-Oncogene Proteins c-akt / genetics
-
Proto-Oncogene Proteins c-akt / immunology*
-
RNA, Messenger / genetics
-
RNA, Messenger / immunology
-
TOR Serine-Threonine Kinases / genetics
-
TOR Serine-Threonine Kinases / immunology*
-
Th17 Cells / immunology*
-
Th17 Cells / pathology
Substances
-
CREM protein, human
-
Crem protein, mouse
-
IL17A protein, human
-
IL17F protein, human
-
Il17a protein, mouse
-
Il17f protein, mouse
-
Interleukin-17
-
RNA, Messenger
-
Cyclic AMP Response Element Modulator
-
MTOR protein, human
-
mTOR protein, mouse
-
Proto-Oncogene Proteins c-akt
-
TOR Serine-Threonine Kinases
-
CAMK4 protein, human
-
Calcium-Calmodulin-Dependent Protein Kinase Type 4
-
Camk4 protein, mouse