Identification of domains in IL-16 critical for biological activity.
IL-16 is a proinflammatory cytokine implicated in the pathogenesis of asthma and other conditions characterized by recruitment of CD4+ T cells to sites of disease. It is postulated that CD4 is an IL-16 receptor, although other receptors or coreceptors may exist. Among several known functions, IL-16 is a chemoattractant factor for CD4+ T cells and it inhibits MLR. We previously reported that an oligopeptide corresponding to the 16 C-terminal residues of human IL-16 inhibits chemoattractant activity. To identify functional domains with greater precision, shorter oligonucleotides containing native or mutated C-terminal IL-16 sequences were tested for IL-16 inhibition. Within the 16 C-terminal residues, the minimal peptide RRKS (corresponding to Arg106 to Ser109) was shown to mediate inhibition of IL-16 chemoattractant activity. Inhibition was lost when either arginine was substituted with alanine. Point mutations in IL-16 revealed that Arg107 is critical for chemoattractant activity, but MLR inhibition was unaffected by mutation of Arg107 or even deletion of the C-terminal tail through Arg106. Deletion of 12 or 22 N-terminal residues of IL-16 had no impact on chemoattractant activity, but MLR inhibition was reduced. Deletion of 16 C-terminal plus 12 N-terminal residues abolished both chemoattractant and MLR-inhibitory activity of IL-16. These data indicate that receptor interactions with IL-16 that activate T cell migration are not identical with those required for MLR inhibition, and suggest that both N-terminal and C-terminal domains in IL-16 participate in receptor binding or activation.
Nicoll
J
J
The Pulmonary Center, Boston University School of Medicine, MA 02118, USA.
Cruikshank
W W
WW
Brazer
W
W
Liu
Y
Y
Center
D M
DM
Kornfeld
H
H
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution / Q000235:genetics / Q000276:immunology; D015153:Blotting, Western; D002464:Cell Migration Inhibition; D002630:Chemotactic Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D019410:Interleukin-16 / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics / Q000502:physiology*; D007959:Lymphocyte Culture Test, Mixed; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000502:physiology; D010446:Peptide Fragments / Q000737:chemistry* / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D011994:Recombinant Proteins / Q000235:genetics / Q000494:pharmacology; D017384:Sequence Deletion; D013601:T-Lymphocytes / Q000276:immunology
D002630:Chemotactic Factors; D007166:Immunosuppressive Agents; D019410:Interleukin-16; D009842:Oligopeptides; D010446:Peptide Fragments; D011994:Recombinant Proteins