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IL16

[Interleukin-16] This factor has been described originally as Lymphocyte chemoattractant factor (LCF), which is produced by CD4(+) and CD8(+) T-cells and acts as a chemoattractant for lymphocytes. The IL16 protein is derived from a much larger biologically inactive precursor (Baier et al, 1997; Bannert et al, 1996). Cleavage of bioactive secreted IL16 from its precursor is mediated by Caspase-3 (Wu et al, 1999). Bannert et al (1999) have cloned the murine gene. Keane et al (1998) have reported a high degree of structural and functional similarity between human and murine IL16. A high level of similarity at the amino acid sequence level is observed also between feline, human, and monkey IL16 (Leutenegger et al, 1998). Kurscher and Yuzaki (1999) have described the identification of NIL16 (Neuronal IL16) as a cytosolic long form of IL16 detected only in neurons.

Zhang et al (2001) have reported that the large proform of human IL16 (631 amino acids) is cleaved into two functional proteins, a C-terminal secreted cytokine and an N-terminal product, which localizes to the nucleus and affects the cell cycle. Chupp et al (1998) have shown that > 70 % of CD4(+) and CD8(+) T-cells constitutively express IL16 protein, which is processed into bioactive secreted IL16 upon cell activation.

IL16 is secreted mainly by CD8(+) lymphocytes (Laberge et al, 1995; Schwab et al, 2001). The protein is produced by B-cells (Sharma et al, 2000; Kaser et al, 2000), neutrophils (Schwab et al, 2001), eosinophils (Laberge et al, 1999; Dunzendorfer et al, 2003; Lim et al, 1996), mast cells (Laberge et al, 1999; Middel et al, 2001; Rumsaeng et al, 1997), monocytes (Elssner et al, 2004), macrophages (Schwab et al, 2001; Reich et al, 2004), microglial cells (Schwab et al, 2001; Guo et al, 2004), dendritic cells (Kaser et al, 1999; Reich et al, 2002), lung epithelial cells (Yoshida et al, 2001; Arima et al, 1999; Little et al, 2003; Cheng et al, 2002; Bellini et al, 1993), keratinocytes (Frezzolini et al, 2004), thyrocytes (Gianoukakis et al, 2003), and fibroblasts from several tissues (Sciaky et al, 2000; Franz et al, 1998; Pritchard et al, 2004). Preformed bioactive IL16 has been shown to be released from CD8(+) T-cells, in contrast to CD4(+) cells, after activation with serotonin or histamine (Laberge et al, 1996, 1995; Gantner et al, 2002).

IL16 is a chemoattractant for a variety of cell types that express the cell surface antigen CD4 (Cruikshank et al, 2000), including CD4(+) T-cells (Cruikshank et al, 1994; Caufour et al, 2001; Hidi et al, 2000; Center and Cruikshank, 1982), Th1 cells (Lynch et al, 2003), dendritic cells (Kaser et al, 2000, 1999), monocytes (Cruikshank et al, 1987), macrophages (Laberge et al, 1999), eosinophils (Cheng et al, 2002; Rand et al, 1991, Ferland et al, 2004), Langerhans cells (Stoitzner et al, 2001). Asadullah et al (2000) have implicated IL16 in growth and skin homing of cutaneous T-cell lymphomas.

Mathy et al (200) have reported that CD14(+) CD4(+) monocytes and maturing macrophages, but not CD4(+) T-cells, secrete IL1-beta, IL6, IL15 and TNF-alpha in response to IL16 stimulation. IL16 upregulates expression of IL2 receptor and CD80, but downregulates CD4 and CD86 surface expression in monocyte-derived macrophages and also reduces expression of CCR5 and CXCR4 (Hermann et al, 1999). IL16 upregulates expression of IL2 receptor and CD83 in monocyte-derived dendritic cells but does not change levels of expression of CD4, CD80 and CD86 in these cells (Hermann et al, 1999).

IL16 has been shown to upregulate IL2 receptor (CD25) on CD4(+) T-cells (Cruikshank et al, 1994, 1987), and thus influences cell activation of these cells, which depends on IL2. Ogasawara et al (1999) have reported that IL16 suppreses mitogen-induced production of IL2 by CD4(+) T-cells. IL16 also induces the transient loss of responsiveness via the T-cell receptor (Cruikshank et al, 1996; Theodore et al, 1996). IL16 acts as both primer and modulator of T-lymphocyte growth (Wilson et al, 2004).

Bandeira-Melo et al (2002) have reported that IL16 promotes release of leukotrienes and IL4 from human eosinophils.

IL16 has been shown to suppress the replication of HIV and SIV (Baier et al, 1995). Idziorek et al (1998) have reported that recombinant human IL16 inhibits HIV-1 replication and protects against cell death by apoptosis. Amiel et al (1999) have reported that IL16 inhibits human immunodeficiency virus replication in cells from infected subjects and that serum IL16 levels drop with disease progression. Truong et al (1999) have reported that IL16 inhibits human immunodeficiency virus type 1 entry and replication in macrophages and in dendritic cells.

Van Drenth et al (2000) have reported that IL16, the natural ligand of CD4, causes desensitization of one of the chemokine receptors, CXCR4, which is a coreceptor for CD4 for binding of HIV-1 gp120 protein. Mashikian et al (1999) have reported that IL16 also causes desensitization of the CCR5 receptor.

Pinsonneault et al (2001) have reported that IL16 inhibits IL5 production by antigen-stimulated T-cells in atopic subjects.

IL16 derived from CD8(+) T-cells has been implicated in the induction of CD4(+) T-cell abnormalities in systemic lupus erythematosus (Lee et al, 1998; Sekigawa et al, 2000). Upregulation of IL16 expression has been implicated in the pathogenesis of chronic intestinal inflammation and could lead to increased secretion of other pro-inflammatory cytokines in Inflammatory bowel disease (Seegert et al, 2001). Hessel et al (1998) have reported that IL16 plays an important role in airway hyper-responsiveness and upregulation of IgE, but is not important for eosinophil accumulation in a mouse model of allergic asthma. Franz et al (1998) have implicated IL16 in rheumatoid arthritis since IL16, produced by synovial fibroblasts, mediates chemoattraction for CD4(+) T-cells in rheumatoid arthritis.

IL16 is generally assumed to utilize CD4 as a receptor (Center et al, 1996). Liu et al (1999) have identified the CD4 domain required for IL16 binding and lymphocyte activation. However, Mathy et al (2000) have reported that CD4 is not required for the functional activity of IL16 in murine monocytes. Their observation that cells from CD4 knock-out mice are as responsive to IL16 as their CD4 wild-type equivalents and that the effects of IL16 cannot be inhibited by soluble CD4 in these mice suggests that another molecule acts as the major receptor. Stoitzner et al (2001) have reported also that IL16 supports the migration of Langerhans cells through mechanisms partly independent of CD4.

LAST MODIFIED: January 2005

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