Interleukin (IL)-16 was first described in 1982 under the name “lymphocyte chemoattractant factor”.1 Since its cloning in 1994,2 the complex structure and biological function of this cytokine has been extensively explored. In 1999, the IL-16 gene was localised to chromosome 15q26.33 but the role of genetic variants of this gene have yet to be explored in human disease.

IL-16 can be produced by a variety of inflammatory cells, including mast cells, eosinophils, mononuclear phagocytes, and CD4+ and CD8+ T cells.4 IL-16 is expressed as an 80 kDa precursor molecule,5 which is processed to active IL-16 by caspase 3.6

Most interestingly, the main receptor for IL-16 appears to be the CD4 molecule (which identifies T helper cells but is also present on monocytes and other phagocytes). It is assumed that interaction with the CD4 molecule is the main event in induction of most IL-16 mediated biological effects although other receptors and co-receptors may exist. The main biological function of IL-16 appears to be recruitment of CD4+ T cells. In addition, IL-16 induces the production of proinflammatory cytokines (that is, tumour necrosis factor, IL-1β, IL-6, and IL-15 by monocytes)7 and can regulate RAG gene expression in CD4+ B cells. The mechanisms of signal transduction of IL-16 are still unclear but appear to involve tyrosine kinases (that is, p56lck) in T cells, the stress activated protein kinases (SAPK) pathway, and activation of the p38 mitogen activated protein kinase (MAPK).8 ,9

Not surprisingly, IL-16 is implicated in the pathophysiology of chronic immune diseases, including allergen induced bronchial asthma, rheumatoid arthritis,10 and Crohn's disease.11 ,12 It has been found to be elevated in both Crohn's disease and ulcerative colitis where a positive correlation between disease activity and IL-16 expression has been found.12 Expression of IL-16 was also upregulated in an animal model of chronic intestinal inflammation and blocking IL-16 activity ameliorates TNBS colitis.11

In this issue of Gut, Middel and colleagues13 analysed the contribution of IL-16 to the pathophysiology of inflammatory bowel disease in an elegant study using a variety of molecular techniques (see page 795). They found that increased production of IL-16 is particularly important in the pathophysiology of the inflammatory lesions in Crohn's disease in comparison with ulcerative colitis. A strong relationship between increased expression of IL-16 in T cells/mast cells and numbers of CD4+ T cells was found. Discrete accumulation of mast cells as well as increased numbers of eosinophils have frequently been seen by pathologists although their contribution to pathophysiology was unexplained until now. The role of these cells in the pathophysiology of Crohn's disease is now explained as important contributors of IL-16.

Recently, three studies have independently identified mutations in the NOD2 gene on chromosome 16q as a primary cause of Crohn's disease in a subset (up to 25%) of patients.14-16 NOD2 is only expressed by monocytes/macrophages and its role in other phagocytes is presently unclear. However, it is not expressed in lymphocytes or epithelial cells. It is currently hypothesised that a mutation in the NOD2 gene impacts the handling of bacterial pathogens by monocytes by alteration in the lipopolysaccharide/NOD2 induced activation of nuclear factor kappa B (NFκB). It is thought that this constitutive defect predisposes patients with Crohn's disease to chronic inflammation, which may be triggered by the commensal flora.

The argument can be made that T cells and hence IL-16 may only play a secondary role in the disease process. The study presented by Middleet al links activation of phagocytes in the pathophysiology of Crohn's disease to strong evidence of a T cell contribution to disease pathophysiology. Increased activation of mononuclear phagocytes that results in the release of proinflammatory cytokines and also IL-16 is directly associated with CD4+ T cell recruitment. As first reports showed increased activation of p38 MAPK in Crohn's disease,17 which may result in increased levels of IL-16, additional molecular data provided by Middleet al strongly supports this interpretation.

IL-16 may be an interesting target to interrupt the loop between mononuclear phagocytes and T cell activation. An important question will be whether mast cells, eosinophils, and other phagocytes also express genes of the NOD2 family. As expression of IL-16 is most likely controlled by NFκB, this cytokine may be a central player in linking the different aspects of Crohn's disease pathophysiology.