Egli, Nicole, Zajonz, Alexandra, Burger, Matthew and Schweighoffer, Tamas (2015) Human CD180 transmits proinflammatory signals via the Pim 1L kinase. PLoS ONE (e01427).

Abstract

Toll-like receptors (TLRs) are important sensors of the innate immune system that recognize conserved structural motifs and activate cells via a kinase cascade. Using a highly specific inhibitor and mRNA knockdown we show that members of the Pim kinase family are required for effective TLR signaling, and identify specifically the membrane bound long form of Pim-1 kinase (Pim 1L) as an active component. Surprisingly, Pim is also required for cytokine production initiated by CD180 that is a discordant member of the TLR family. So far the CD180/MD 1 complex was thought of being incapable of independent signaling, and also no downstream molecular pathways were mapped, since CD180 itself lacks the TLR-like intracellular adaptor domains that are inevitable for signal transduction by TLRs. We find that specifically the long form Pim 1L is directed to the cell membrane where it colocalizes and associates with CD180. In primary human B cells, which are the main cells expressing CD180 in man, cross-linking of CD180 by monoclonal antibodies stimulates survival and proliferation that can be abrogated by specific Pim inhibitors. CD180 obtains thus autonomous signaling capabilities by forming a complex with Pim 1L, and may contribute to 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 concomitant B cell activation, such as lupus erythematosus or myasthenia gravis.

Item Type:	Article
Date Deposited:	20 Nov 2015 00:45
Last Modified:	20 Nov 2015 00:45
URI:	https://oak.novartis.com/id/eprint/24292