Effect of interleukin-16-blocking peptide on parameters of allergic asthma in a murine model
Introduction
Human allergic asthma is characterised by airway hyperresponsiveness and infiltration of lymphocytes and eosinophils in the lungs (Corrigan and Kay, 1992). There is increasing evidence that CD4+ T cells play a crucial role in orchestrating these different phenomena by producing Th2-type cytokines, including interleukin-4 and interleukin-5 Corrigan and Kay, 1992, Virchow et al., 1996.
Besides interleukin-4 and interleukin-5, many other cytokines have been associated with the pathology of asthma, one of them being interleukin-16 (Center et al., 1996). Interleukin-16 has been demonstrated to use the CD4 molecule as its receptor. Upon binding and cross-linking of CD4 molecules, several second messengers, including p56lck and protein kinase C, are activated Haughn et al., 1992, Ryan et al., 1995, Racioppi et al., 1996. Furthermore, interleukin-16 can evoke different functional responses in CD4+ cells. One of the most extensively described actions of CD4 cross-linking by interleukin-16 is the induction of chemotaxis in vitro (Center and Cruikshank, 1982). It has been demonstrated that interleukin-16 can induce such responses in various CD4+ cells, including eosinophils, monocytes and T helper cells Center et al., 1995, Center et al., 1996. Other biological effects of interleukin-16 include induction of interleukin-2R expression and up-regulation of MHC-II expression in human lymphocytes Center et al., 1995, Center et al., 1996.
Both CD4+ and CD8+ T cells constitutively express messenger RNA for interleukin-16 and the biologically active protein is secreted from CD8+ T cells after stimulation with either histamine or 5-hydroxytryptamine (5-HT) Laberge et al., 1995, Laberge et al., 1996. Furthermore, CD4+ T cells release interleukin-16 after mitogen, antigen or anti-CD3 stimulation (Center et al., 1996). Bioactive interleukin-16 can also be produced by eosinophils, mast cells and epithelial cells Bellini et al., 1993, Lim et al., 1996, Rumsaeng et al., 1997. These data suggest that interleukin-16 may be involved in the pathophysiology of asthma. Indeed, in patients with allergic asthma as well as in a murine model of allergic asthma, there is interleukin-16 expression in epithelial cells and bioactive interleukin-16 was found in bronchoalveolar lavage fluid after antigen challenge Laberge et al., 1997, Hessel et al., 1998. Interestingly, inhibition of endogenous interleukin-16 by intraperitoneal administration of antibodies to interleukin-16 has been demonstrated to partially decrease airway hyperresponsiveness but not to affect the number of eosinophils in bronchoalveolar lavage fluid in a murine model of allergic asthma (Hessel et al., 1998).
In a previous study, Keane et al. (1998) demonstrated that peptide 3, which is based on the predicted amino acid sequence of one of the hydrophilic C-terminal regions of interleukin-16, is capable of partially inhibiting recombinant human interleukin-16-induced chemotaxis of peripheral blood mononuclear cells. They also demonstrated that peptide 3 could displace binding of antibodies (OKT4) to CD4 molecules. These data suggest that the C-terminal hydrophilic domain of interleukin-16 is involved in binding to CD4 and is critical for induction of chemotaxis in CD4+ cells (Hessel et al., 1998). Additionally, these data suggest that the peptide might inhibit interleukin-16-induced activity by binding to CD4 molecules, thereby preventing cross-linking of CD4 molecules by interleukin-16. Finally, sequence homology of murine and human interleukin-16 is over 80% and cross-specificity is nearly 100% since identical effects were observed on migration of human or murine CD4+ T lymphocytes induced by either recombinant human or recombinant murine interleukin-16 and this chemoattracting activity could be blocked by anti-human interleukin-16 mAb (clone 14.1, Keane et al., 1998).
In the present study, we examined the effect of various peptides based on the predicted amino acid sequence of interleukin-16 on recombinant human interleukin-16-induced chemotaxis of lymphocytes in vitro. Next, we examined the effects of intranasal administration of these peptides on airway hyperresponsiveness and eosinophilia in a murine model of asthma. In addition, we compared the effects of local administration of these peptides with those of administration of antibodies to interleukin-16 on the same parameters.
Section snippets
Peptides and antibodies
Synthetic oligopeptides corresponding to three hydrophilic domains identified within the human interleukin-16 sequence were used in this study. The single letter amino acid codes of the different peptides are: MPDLNSSTDSA (based on amino acids 502–512, Fig. 1), designated peptide 1, AASEQSETVQPGDEIL (based on amino acids 569–584, Fig. 1), designated peptide 2 and RRKSLQSKETTAAGDS, peptide 3 (based on amino acids 616–631, Fig. 1). Peptides were generously provided by Dr. W.W. Cruikshank and
Chemotaxis assay
The effects of peptides 1, 2 and 3 were measured on murine recombinant interleukin-16-induced mouse lymphocyte motility. Lymphocyte motility induced by medium alone was taken as 100%. The interleukin-16-induced chemoattractive activity amounted to 203±7%, which was significantly (P<0.05) inhibited by peptide 3 to 124±8% (Fig. 2). Incubation of the target cells with either peptide 1 or 2 did not result in any detectable decrease in interleukin-16-induced chemotaxis (Fig. 2). Furthermore,
Discussion
The study now described showed that peptide 3, which is based on the predicted amino acid sequence of recombinant human interleukin-16 is capable of inhibiting recombinant murine interleukin-16-induced chemotaxis of murine splenocytes. Peptide 3 also markedly inhibited antigen-induced airway hyperresponsiveness in a murine model of allergic asthma, whereas eosinophilic infiltration was not significantly altered. Furthermore, we demonstrated that local administration of antibodies to
Acknowledgements
Financial support was provided for JJB from Glaxo-Wellcome, Zeist, The Netherlands. WWC is a recipient of the Career Investigator Award from the American Lung Association.
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