A team led by scientists at The Scripps Research Institute (TSRI) has identified key signaling proteins in the inflammation process that contribute to the development of inflammatory diseases such as rheumatoid arthritis.
“We hope our approach will lead to the development of drugs that augment current anti-inflammatory strategies, ” said TSRI Assistant Professor Young Jun Kang, in the October 10, 2013 news release. Dr. Kang was the principal investigator for the new study, which was reported recently in the journal Science Signaling.
As Dr. Kang and other investigators have shown, this type of inflammation typically has an early, acute phase and a late, sustained phase, the two phases being driven by distinct clusters of signaling molecules. Dr. Kang’s approach for most of the past ten years has been to work on suppressing the late phase while leaving the early phase intact to fight ordinary infections. In a study published in 2007 when he was a postdoctoral fellow at TSRI, Dr. Kang identified an immune cell protein called 4-1BBL as a critical factor in the late phase of a common type of inflammation triggered by the receptor TLR4. In the new study, Dr. Kang and his colleagues examined 4-1BBL and its signaling partners in more detail to better understand the pathway and to find suitable drug targets.
In a series of experiments with cultured cells, Dr. Kang’s colleagues Research Associates Jianhui Ma and Bo-Ram Bang were able to show that in late-phase, TLR4-triggered inflammation, 4-1BBL depends heavily on two other key proteins, TIRAP and IRAK2.
TIRAP appeared to be particularly important. Blocking its interaction with 4-1BBL by removing its gene from cells or by applying a specific chemical inhibitor, reduced late-phase inflammation—as shown by a big drop in TNF-α production. In mice with TLR4-triggered sepsis, inhibiting TIRAP again worked to reduce TNF-α levels and extended the animals’ survival.
As a next step, Dr. Kang and his colleagues will now test anti-inflammation therapeutic strategies, such as small chemicals and recombinant proteins that target the TIRAP-4-1BBL interaction, with the hope of eventually being able to develop a new class of anti-inflammatory therapy.
As Dr. Kang notes, current anti-inflammatory therapies typically aim to reduce TNF-α activity, for example with antibodies, after the protein has already been produced. His strategy targets an earlier part of the process and thereby suppresses TNF-α production.
