The gene encoding leucine-rich repeat kinase 2 (LRRK2) comprises a major risk factor for Parkinson's disease. Recently, it has emerged that LRRK2 plays important roles in the immune system. LRRK2 is induced by interferon-c (IFNc) in monocytes, but the signaling pathway is not known. Here, we show that IFN-c-mediated induction of LRRK2 was suppressed by pharmacological inhibition and RNA interference of the extracellular signal-regulated kinase 5 (ERK5). This was confirmed by LRRK2 immunostaining, which also revealed that the morphological responses to IFN-c were suppressed by ERK5 inhibitor treatment. Both human acute monocytic leukemia THP-1 cells and human peripheral blood monocytes stimulated the ERK5-LRRK2 pathway after differentiation into macrophages. Thus, LRRK2 is induced via a novel, ERK5-dependent IFN-c signal transduction pathway, pointing to new functions of ERK5 and LRRK2 in human macrophages. Keywords: extracellular signal-regulated kinase, interferon, leucine-rich repeat kinase, macrophages, mitogen-activated protein kinase, signal transduction. M€ uller Str. 27, 72076 T€ ubingen, Germany. E-mail: philipp.kahle@ uni-tuebingen.de Abbreviations used: ERK5, extracellular signal-regulated kinase 5; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; GM-CSF, granulocyte-macrophage colony-stimulating factor; HRP, horseradish peroxidase; IFN-c, interferon-c; IN, inhibitor; JAK, Janus kinase; KD, knockdown; LRRK2, leucine-rich repeat kinase 2; MAPK, mitogenactivated kinase; MDM, monocyte-derived macrophage; PD, Parkinson's disease; PMA, phorbol-12-myristate-13-acetate; RNAi, RNA interference; shRNA, small hairpin RNA; STAT1, signal transducer and activator of transcription 1; TBST, Tris-buffered saline + 0.1% Tween 20.
