Abstract
Toll-like receptors (TLRs) are important sensors of the innate immune system that recognize conserved structural motifs and activate cells via a downstream signaling cascade. The CD180/MD1 molecular complex is an unusual member of the TLR family, since it lacks the components that are normally required for signal transduction by other TLRs. Therefore the CD180/MD 1 complex has been considered of being incapable of independently initiating cellular signals. Using chemogenetic approaches we identified specifically the membrane bound long form of PIM-1 kinase, PIM-1L as the mediator of CD180-dependent signaling. A dominant negative isoform of PIM-1L, but not of other PIM kinases, inhibited signaling elicited by cross-linking of CD180, and this effect was phenocopied by PIM inhibitors. PIM-1L was directed to the cell membrane by its N-terminal extension, where it colocalized and physically associated with CD180. Triggering CD180 also induced increased phosphorylation of the anti-apoptotic protein BAD in a PIM kinase-dependent fashion. Also in primary human B cells, which are the main cells expressing CD180 in man, cross-linking of CD180 by monoclonal antibodies stimulated cell survival and proliferation that was abrogated by specific inhibitors. By associating with PIM-1L, CD180 can thus obtain autonomous signaling capabilities, and this complex is then channeling inflammatory signals into B cell survival programs. Pharmacological inhibition of PIM-1 should therefore provide novel therapeutic options in diseases that respond to innate immune stimulation with subsequently increased B cell activity, such as lupus erythematosus or myasthenia gravis.
Highlights
Medicines used for targeted therapies achieved clinical success due to their very high efficacy and selectivity
Cytokine release induced by Toll-like receptors (TLRs) family members depends on intact PIM kinase activity
Our data show that CD180 is capable of initiating signals independently from the known TLRdependent pathways via the PIM-1L kinase isoform
Summary
Medicines used for targeted therapies achieved clinical success due to their very high efficacy and selectivity. Kinase inhibitors represent a successful class of targeted drugs, and many of them can offer a nearly complete biochemical inhibition of the critical target protein, while effects on other non-target molecules are minimal or absent. Our recently discovered series of PIM kinase inhibitors are an eminent example of such selective and effective molecules. Compound 5c of the series inhibits all three members of the PIM kinases with picomolar biochemical and nanomolar cellular potency, is highly selective against other targets, and at the same time displays favorable cellular and physico-chemical properties [1]. We selected Compound 5c as a chemical probe that we used to reassess the role of PIM kinases beyond cancer, with a focus on a broad range of immune processes. As part of an NFkB-driven loop, Pim-2 was considered as a candidate that could phosphorylate and amplify the proinflammatory action of the Tpl2/Cot kinase in mice [3]
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