Structure of a Potential Therapeutic Antibody Bound to Interleukin-16 (IL-16)

Abstract

Interleukin-16 (IL-16) is reported to be a chemoattractant cytokine and modulator of T-cell activation, and has been proposed as a ligand for the co-receptor CD4. The secreted active form of IL-16 has been detected at sites of T H 1-mediated inflammation, such as those seen in autoimmune diseases, ischemic reperfusion injury (IRI), and tissue transplant rejection. Neutralization of IL-16 recruitment to its receptor, using an anti-IL16 antibody, has been shown to significantly attenuate inflammation and disease pathology in IRI, as well as in some autoimmune diseases. Interleukin-16 (also known as lymphocyte chemoattractant factor) was first described in 1982 as a T-cell chemoattractant factor produced by antigen and mitogen-stimulated lymphocytes (1). An array of immune and non-immune cells are now known to express IL-16 as one aspect of an inflammatory response, including CD4 ϩ and CD8 ϩ T cells, eosinophils, monocytes, mast cells, and dendritic cells (2-5). In addition, IL-16 has been reported to promote the entry of resting CD4 ϩ T cells into the cell cycle, and the up-regulation of IL-2 receptor and major histocompatibility (MHC) class II proteins on cell surfaces (6, 7).Human 4 is expressed as a 631-amino acid precursor protein and contains three PDZ domains, along with an N-terminal CcN motif, encompassing both CK2 and cdc2 kinase phosphorylation sites, a nuclear localization signal, and an Src homology 3 binding motif (Fig. 1A) (8, 9). Following cytosolic proteolysis of hIL-16 by caspase-3, a 121-amino acid fragment encompassing the C-terminal PDZ domain (residues 527-619) is secreted as the mature form of IL-16 (10). Secreted IL-16 has been reported to bind to CD4 with relatively high affinity (6,11,12), which is consistent with IL-16 functioning as a pro-inflammatory cytokine. The protein is reported to have two major effects on CD4 ϩ cells: chemoattraction, preferentially of T H 1 cells, and inhibition of CD3/T-cell mediated activation, preferentially of T H 2 cells (13). Co-incubation of CD4 ϩ cells with an anti-CD4 antibody (OKT4) is reported to lead to a reduction in the magnitude of IL-16-induced cell migration by monocytes (11). The protein CD4 contains four immunoglobulin (Ig)-like domains (D1-D4), and CD4-derived peptide inhibition studies of IL-16-mediated chemotaxis suggested that IL-16 binds to CD4 D4 (6). There is also evidence to suggest that chemokine receptor 5, which is expressed on the surface of T H 1 cells, enhances the binding of IL-16 to the co-receptor (14).Interestingly, the chemotactic activity of hIL-16 is not associated with a characteristic chemokine structural motif (15, 16). The solution structure of mature hIL-16 has been reported and showed the chemokine to contain a classical PDZ domain, consisting of a central up and down ␤-sandwich, adjacent to an ␣-helix (17). PDZ domains typically assist in the assembly of multiprotein signaling complexes, by binding peptides in a groove between the ␣1-helix and ␤2-strand, in a process known

In major dysmood disorder, physiosomatic, chronic fatigue and fibromyalgia symptoms are driven by immune activation and increased immune-associated neurotoxicity

“…IL-16 and other proinflammatory cytokines are associated with elevated depression and neuroticism scores in hepatitis C patients receiving cytokine-based immunotherapy 58 . 59 , 60 . IL-16 induces T cell signaling via the CD4 molecule on Th cells, resulting in the upregulation of activation markers such as HLA-DR + and CD25 + cells.…”

In severe first episode major depressive disorder, psychosomatic, chronic fatigue syndrome, and fibromyalgia symptoms are driven by immune activation and increased immune-associated neurotoxicity.

“…IL-16 and other proin ammatory cytokines are associated with elevated depression and neuroticism scores in hepatitis C patients receiving cytokine-based immunotherapy 53 . 54,55 . IL-16 induces T cell signaling via the CD4 molecule on T helper cells, resulting in the upregulation of activation markers such as HLA-DR + and CD25 + cells.…”

High-Dose Dexamethasone Alters the Increase in Interleukin-16 Level in Adult Immune Thrombocytopenia

“…A study reported that IL-16 is necessary for B lymphocytes to attract dendritic cells and Th1 cells ( 25 ). A novel monoclonal anti-IL-16 antibody called 14.1, that combines with IL-16 and induces a conformational change in the IL-16 PDZ domain has been recently reported ( 50 ). When incubated with CD4 + cells, the 14.1 antibody was shown to reduce the Th1-type inflammatory response.…”