IL-6 biology: implications for clinical targeting in rheumatic disease

IL-6 can signal via the membrane-bound and the soluble IL-6 receptor (IL-6R); classic signalling via the membrane-bound receptor is regenerative and protects from bacterial infections, whereas trans-signalling via the soluble receptor is proinflammatoryThe soluble gp130Fc fusion protein specifically blocks IL-6 trans-signalling without affecting classic signallingPreclinical models strongly suggest the efficacy of IL-6-directed therapies for a variety of immunological conditionsThe approval and use of tocilizumab, a first-in-class human monoclonal antibody directed at IL-6R, has demonstrated that this strategy is both highly effective and safeNew agents with unique bioengineering features targeting either IL-6 or the soluble IL-6R, with varying selectivity for classic signalling and trans-signalling pathways, are entering clinical trials and offer alternative strategies for IL-6-based therapiesSelective IL-6-based therapeutic targeting has several unique toxicity signatures, including paradoxical effects on surrogate markers of cardiovascular risk, and awaits clinical studies to determine net effects on morbidity and mortality