Kinase RIP3 Is Dispensable for Normal NF-κBs, Signaling by the B-Cell and T-Cell Receptors, Tumor Necrosis Factor Receptor 1, and Toll-Like Receptors 2 and 4

TLDR

RIP3, a RIP kinase family member expressed in embryonic and adult hematopoietic tissues, has been implicated in apoptosis and NF‑κB signaling, yet its precise influence on NF‑κB activation remains controversial. The authors generated RIP3‑deficient mice to determine whether RIP3 is required for normal development and NF‑κB signaling. RIP3‑deficient mice and cells displayed normal development, apoptotic sensitivity, NF‑κB activation in response to TNF, B‑ and T‑cell receptor cross‑linking, TLR2/4 ligands, normal antibody production after T‑dependent immunization, and normal cytokine release after LPS, indicating RIP3 is not an essential modulator of NF‑κB signaling downstream of these receptors.

Abstract

ABSTRACT RIP3 is a member of the RIP kinase family. It is expressed in the embryo and in multiple adult tissues, including most hemopoietic cell lineages. Several studies have implicated RIP3 in the regulation of apoptosis and NF-κB signaling, but whether RIP3 promotes or attenuates activation of the NF-κB family of transcription factors has been controversial. We have generated RIP3-deficient mice by gene targeting and find RIP3 to be dispensable for normal mouse development. RIP3-deficient cells showed normal sensitivity to a variety of apoptotic stimuli and were indistinguishable from wild-type cells in their ability to activate NF-κB signaling in response to the following: human tumor necrosis factor (TNF), which selectively engages mouse TNF receptor 1; cross-linking of the B- or T-cell antigen receptors; peptidoglycan, which activates Toll-like receptor 2; and lipopolysaccharide (LPS), which stimulates Toll-like receptor 4. Consistent with these observations, RIP3-deficient mice exhibited normal antibody production after immunization with a T-dependent antigen and normal interleukin-1β (IL-1β), IL-6, and TNF production after LPS treatment. Thus, we can exclude RIP3 as an essential modulator of NF-κB signaling downstream of several receptor systems.