IL-35, as a newly proposed homeostasis-associated molecular pattern, plays three major functions including anti-inflammatory initiator, effector, and blocker in cardiovascular diseases.

IL-35 is a new anti-inflammatory cytokine identified in 2007, which inhibits inflammation and immune responses by inducing regulatory T cells and regulatory B cells and suppressing effector T cells and macrophages. The unique initiator and effector anti-inflammatory properties of IL-35 bring tremendous interest in investigating its role during cardiovascular disease (CVD) development, in which inflammatory processes are firmly established as central to its development and complications. In this review, we update recent understanding of how IL-35 is produced and regulated in the cells. In addition, we outline the signaling pathways affected by IL-35 in different cell types. Furthermore, we summarize the roles of IL-35 in atherosclerosis, diabetes, and sepsis. We propose a new working model that IL-35 and its receptors are novel homeostasis-associated molecular pattern (HAMP) and HAMP receptors, respectively, which explains the complex nature of IL-35 signaling as an anti-inflammatory initiator, effector and blocker. Thorough understanding of this topic is significant towards development of new anti-inflammatory therapies against CVDs and other diseases. (total words: 163).