Structural basis of signaling complex inhibition by IL-6 domain-swapped dimers.

Interleukin-6 (IL-6) is a multifaceted cytokine essential in many immune system processes and their regulation. It also plays a key role in hematopoiesis, and in triggering the acute phase reaction. IL-6 overproduction is critical in chronic inflammation associated with autoimmune diseases like rheumatoid arthritis and contributes to cytokine storms in COVID-19 patients. Over 20 years ago, researchers proposed that IL-6, which is typically monomeric, can also form dimers via a domain-swap mechanism, with indirect evidence supporting their existence. The physiological significance of IL-6 dimers was shown in B-cell chronic lymphocytic leukemia. However, no structures have been reported so far. Here, we present the crystal structure of an IL-6 domain-swapped dimer that computational approaches could not predict. The structure explains why the IL-6 dimer is antagonistic to the IL-6 monomer in signaling complex formation and provides insights for IL-6 targeted therapies.