Special issue on Interleukin-6 (IL-6)

Cytokines are essential modulators of the immune response. In the last decade there has been a number of cytokines considered targets for the development of biological therapies with the goal of blocking their activities and modulate the course of the immune response, primarily in the context of inflammatory diseases. IL-6 was first identified in the mid-1980s [1], but for almost two decades the enthusiasm for this cytokine as a potential active molecule and target for diverse diseases was not excessively high. However, it is now becoming clear that IL-6 plays an active role in modulating the immune response, and it has emerged as another successful target for a number of diseases such as inflammatory diseases [2]. Moreover, evidence is growing that IL-6 can also contribute to less expected diseases such as different types of cancer, neurological diseases or metabolic syndromes. Whether this effect of IL-6 is dependent or independent of its effect on the immune response remains to be addressed. In this special issue we provide six reviews that summarize what is known about the regulation, the role and mechanisms of IL-6 in a number of these diseases such as autoimmune diseases, colon cancer, neurodegenerative diseases and asthma. The first review of the issue is by T. Kishimoto, who identified and cloned IL-6, IL-6R and gp130. Considering the clinical data showing persistent elevated levels of IL-6 in various autoimmune and inflammatory diseases and the data from mouse models suggesting an active role of IL-6 in the pathogenesis of these diseases, Kishimoto decided to go from bench to bed, and develop a blocking humanized anti-IL6R antibody (tocilizumab) that could be used as therapy for those inflammatory diseases. The success of such a therapy is evident with its approval worldwide for the treatment of rheumatoid arthritis and other autoimmune diseases. Kishimoto and co-worker summarize the active role that this cytokine has in a number of inflammatory diseases, and the results from the clinical trials and studies where IL-6R is the therapeutic target [3]. In addition to the signaling through the membrane-bound IL-6R, IL-6 can provide signaling to cells lacking IL-6R through its binding to the soluble IL-6R (sIL-6R) and association with gp130, pathway known as trans-signaling of IL-6. S. Rose-John, a pioneer in this alternative IL-6 signaling pathway, describes here the evidences to support different functions for the trans-signaling pathway (pro-inflammatory) and the conventional pathway (anti-inflammatory) of IL-6 [4]. Moreover, the review also provides an update of novel therapies for IL-6 based on the trans-signaling pathways. Although for long it has been known that the levels of IL-6 in serum were elevated in a number of cancers and that IL-6 was expressed in tumor cells, it has not been until the last five years when a role of IL-6 in cancer development or progression was considered. Indeed, in the early-mid 1990’s, instead of IL-6 being considered as a target in cancer treatment, there were several clinical trials administrating recombinant IL-6 in patients with breast, ovarian, prostate cancers among others. However, the association of IL-6 with poor prognosis it is now becoming evident in some types of cancer, and the concept of IL-6 being a potential target in cancer treatment instead of a therapy is emerging. The review by Neurath and Ivyspring