IL-6 induces signaling through a cell surface heterodimeric receptor complex composed of a
ligand binding subunit (IL-6 R alpha) and a signal transducing subunit (gp130). IL-6 binds to
IL-6 R alpha, triggering IL-6 R alpha association with gp130 and gp130 dimerization (39). gp130 is also a
component of the receptors for CLC, CNTF, CT-1, IL-11, IL-27, LIF, and OSM (40). Soluble forms of
IL-6 R alpha are generated by both alternative splicing and proteolytic cleavage (5). In a mechanism
known as trans-signaling, complexes of soluble IL-6 and IL-6 R alpha elicit responses from gp130-
expressing cells that lack cell surface IL-6 R alpha (5). Trans-signaling enables a wider range of
cell types to respond to IL-6, as the expression of gp130 is ubiquitous, while that of IL-6 R alpha is
predominantly restricted to hepatocytes, monocytes, and resting lymphocytes (2, 5). Soluble
splice forms of gp130 block trans-signaling from IL-6/IL-6 R alpha but not from other cytokines that
use gp130 as a co-receptor (5, 41).
IL-6, along with TNF-alpha and IL-1, drives the acute inflammatory response. IL-6 is almost solely
responsible for fever and the acute phase response in the liver, and it is important in the
transition from acute inflammation to either acquired immunity or chronic inflammatory
disease (1-5). When dysregulated, it contributes to chronic inflammation in conditions
such as obesity, insulin resistance, inflammatory bowel disease, arthritis, and sepsis (2, 5).
IL-6 modulates bone resorption and is a major effector of inflammatory joint destruction
in rheumatoid arthritis through its promotion of Th17 cell development and activity (1).
It contributes to atherosclerotic plaque development and destabilization as well as the
development of inflammation-associated carcinogenesis (1, 2). IL-6 can also function as an
anti-inflammatory molecule, as in skeletal muscle where it is secreted in response to exercise
(2). In addition, it enhances hematopoietic stem cell proliferation and the differentiation of
memory B cells and plasma cells (42).
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