Interleukin-6: structure-function relationships.
Interleukin-6 (IL-6) is a multifunctional cytokine that plays a central role in host defense due to its wide range of immune and hematopoietic activities and its potent ability to induce the acute phase response. Overexpression of IL-6 has been implicated in the pathology of a number of diseases including multiple myeloma, rheumatoid arthritis, Castleman's disease, psoriasis, and post-menopausal osteoporosis. Hence, selective antagonists of IL-6 action may offer therapeutic benefits. IL-6 is a member of the family of cytokines that includes interleukin-11, leukemia inhibitory factor, oncostatin M, cardiotrophin-1, and ciliary neurotrophic factor. Like the other members of this family, IL-6 induces growth or differentiation via a receptor-system that involves a specific receptor and the use of a shared signaling subunit, gp130. Identification of the regions of IL-6 that are involved in the interactions with the IL-6 receptor, and gp130 is an important first step in the rational manipulation of the effects of this cytokine for therapeutic benefit. In this review, we focus on the sites on IL-6 which interact with its low-affinity specific receptor, the IL-6 receptor, and the high-affinity converter gp130. A tentative model for the IL-6 hexameric receptor ligand complex is presented and discussed with respect to the mechanism of action of the other members of the IL-6 family of cytokines.
Simpson
R J
RJ
Joint Protein Structure Laboratory, Ludwig Institute for Cancer Research, (Melbourne Tumour Biology Branch), Parkville, Victoria, Australia. simpson@licre.ludwig.edu.au
Hammacher
A
A
Smith
D K
DK
Matthews
J M
JM
Ward
L D
LD
D000595:Amino Acid Sequence; D000818:Animals; D015703:Antigens, CD / Q000737:chemistry* / Q000502:physiology*; D001172:Arthritis, Rheumatoid / Q000276:immunology; D005871:Castleman Disease / Q000276:immunology; D002874:Chromosome Mapping; D002897:Chromosomes, Human, Pair 7; D016207:Cytokines / Q000502:physiology; D005260:Female; D013006:Growth Hormone / Q000737:chemistry; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis / Q000737:chemistry* / Q000502:physiology*; D008954:Models, Biological; D008961:Models, Structural; D008969:Molecular Sequence Data; D009101:Multiple Myeloma / Q000276:immunology; D015663:Osteoporosis, Postmenopausal / Q000276:immunology; D017433:Protein Structure, Secondary; D011565:Psoriasis / Q000276:immunology; D018123:Receptors, Interleukin / Q000737:chemistry* / Q000502:physiology*; D019947:Receptors, Interleukin-6; D011986:Receptors, Somatotropin / Q000737:chemistry; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid
D015703:Antigens, CD; D016207:Cytokines; D015850:Interleukin-6; D018123:Receptors, Interleukin; D019947:Receptors, Interleukin-6; D011986:Receptors, Somatotropin; D013006:Growth Hormone