title: Dual Inhibition of Rip2 and IRAK1/4 Regulates IL-1β and IL-6 in Sarcoidosis Alveolar Macrophages and Peripheral Blood Mononuclear Cells.
abstract: Sarcoidosis is a multisystem granulomatous disease of unknown etiology that primarily affects the lungs. Our previous work indicates that activation of p38 plays a pivotal role in sarcoidosis inflammatory response. Therefore, we investigated the upstream kinase responsible for activation of p38 in sarcoidosis alveolar macrophages (AMs) and PBMCs. We identified that sustained p38 phosphorylation in sarcoidosis AMs and PBMCs is associated with active MAPK kinase 4 but not with MAPK kinase 3/6. Additionally, we found that sarcoidosis AMs exhibit a higher expression of IRAK1, IRAK-M, and receptor interacting protein 2 (Rip2). Surprisingly, ex vivo treatment of sarcoidosis AMs or PBMCs with IRAK1/4 inhibitor led to a significant increase in IL-1β mRNA expression both spontaneously and in response to TLR2 ligand. However, a combination of Rip2 and IRAK-1/4 inhibitors significantly decreased both IL-1β and IL-6 production in sarcoidosis PBMCs and moderately in AMs. Importantly, a combination of Rip2 and IRAK-1/4 inhibitors led to decreased IFN-γ and IL-6 and decreased percentage of activated CD4(+)CD25(+) cells in PBMCs. These data suggest that in sarcoidosis, both pathways, namely IRAK and Rip2, are deregulated. Targeted modulation of Rip2 and IRAK pathways may prove to be a novel treatment for sarcoidosis.
authors.affiliation: Division of Pulmonary & Critical Care and Sleep Medicine, Department of Internal Medicine, Wayne State University School of Medicine and Detroit Medical Center, Detroit, MI 48201; and.
authors.forename: Jaya
authors.identifier: 0000-0001-6557-6500
authors.initials: J
authors.lastname: Talreja
authors.affiliation: Division of Pulmonary & Critical Care and Sleep Medicine, Department of Internal Medicine, Wayne State University School of Medicine and Detroit Medical Center, Detroit, MI 48201; and.
authors.forename: Harvinder
authors.identifier: 0000-0002-1780-9207
authors.initials: H
authors.lastname: Talwar
authors.affiliation: Division of Pulmonary & Critical Care and Sleep Medicine, Department of Internal Medicine, Wayne State University School of Medicine and Detroit Medical Center, Detroit, MI 48201; and.
authors.forename: Nisar
authors.initials: N
authors.lastname: Ahmad
authors.affiliation: Division of Pulmonary & Critical Care and Sleep Medicine, Department of Internal Medicine, Wayne State University School of Medicine and Detroit Medical Center, Detroit, MI 48201; and.
authors.forename: Ruchi
authors.initials: R
authors.lastname: Rastogi
authors.affiliation: Division of Pulmonary & Critical Care and Sleep Medicine, Department of Internal Medicine, Wayne State University School of Medicine and Detroit Medical Center, Detroit, MI 48201; and Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI 48201 ay6003@wayne.edu.
authors.forename: Lobelia
authors.identifier: 0000-0002-3327-2585
authors.initials: L
authors.lastname: Samavati
mesh_terms: D015153:Blotting, Western; D002470:Cell Survival; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D053592:Interleukin-1 Receptor-Associated Kinases / Q000378:metabolism*; D053583:Interleukin-1beta / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology*; D016676:Macrophages, Alveolar / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2 / Q000378:metabolism*; D017565:Sarcoidosis, Pulmonary / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
chemical_list: C508600:IL6 protein, human; D053583:Interleukin-1beta; D015850:Interleukin-6; C507768:IRAK1 protein, human; C507773:IRAK4 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases; C506253:RIPK2 protein, human; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2