Extracellular cyclophilins contribute to the regulation of inflammatory responses.

The main regulators of leukocyte trafficking during inflammatory responses are chemokines. However, another class of recently identified chemotactic agents is extracellular cyclophilins, the proteins mostly known as receptors for the immunosuppressive drug, cyclosporine A. Cyclophilins can induce leukocyte chemotaxis in vitro and have been detected at elevated levels in inflamed tissues, suggesting that they might contribute to inflammatory responses. We recently identified CD147 as the main signaling receptor for cyclophilin A. In the current study we examined the contribution of cyclophilin-CD147 interactions to inflammatory responses in vivo using a mouse model of acute lung injury. Blocking cyclophilin-CD147 interactions by targeting CD147 (using anti-CD147 Ab) or cyclophilin (using nonimmunosuppressive cyclosporine A analog) reduced tissue neutrophilia by up to 50%, with a concurrent decrease in tissue pathology. These findings are the first to demonstrate the significant contribution of cyclophilins to inflammatory responses and provide a potentially novel approach for reducing inflammation-mediated diseases

The biology of A20-binding inhibitors of NF-κB activation (ABINs)

The family of A20‑Binding Inhibitors of NF‑kB (ABINs) consists of three proteins, ABIN‑1, ABIN‑2 and ABIN‑3, which were originally identified as A20‑binding proteins and inhibitors of cytokines and Lipopolysaccharide (LPS) induced NF‑kB activation. ABIN family members have limited sequence homology in a number of short regions that mediate A20‑binding, ubiquitin‑binding, and NF‑kB inhibition. The functional role of A20 binding to ABINs remains unclear, although an adaptor function has been suggested. ABIN‑1 and ABIN‑3 expression is upregulated when cells are triggered by NF‑kB‑activating stimuli, suggesting a role for these ABINs in a negative feedback regulation of NF‑kB signaling. Additional ABIN functions have been reported such as inhibition of TNF‑induced hepatocyte apoptosis, regulation of HIV‑1 replication for ABIN‑1, and Tumor Progression Locus 2 (TPL‑2)‑mediated Extracellular signal‑Regulated Kinase (ERK) activation for ABIN‑2. In mice, ABIN‑1 overexpression reduces allergic airway inflammation and TNF‑mediated liver injury, ABIN‑2 overexpression delays liver regeneration, and ABIN‑3 overexpression partially protects against LPS‑induced acute liver failure. Analysis of mice deficient in ABIN‑1 or ABIN‑2 demonstrates the important immune regulatory function of ABINs. Future studies should clarify the functional implication of the A20‑ABIN interaction in supporting ABINs’ mechanisms of action