Calcitonin gene-related peptide induces IL-8 synthesis in human corneal epithelial cells.
Calcitonin gene-related peptide (CGRP), a neuropeptide with proinflammatory activities, is released from termini of corneal sensory neurons in response to pain stimuli. Because neutrophil infiltration of the clear corneal surface is a hallmark of corneal inflammation in the human eye, we determined whether CGRP can bind to human corneal epithelial cells (HCEC) and induce expression of the neutrophil chemotactic protein IL-8. It was found that HCEC specifically bound CGRP in a saturable manner with a Kd of 2.0 x 10-9 M. Exposure of HCEC to CGRP induced a significant increase in intracellular cAMP levels and enhanced IL-8 synthesis nearly 4-fold. The capacity of CGRP to stimulate cAMP and IL-8 synthesis was abrogated in the presence of the CGRP receptor antagonist CGRP8-37. CGRP stimulation had no effect on the half-life of IL-8 mRNA while increasing IL-8 pre-mRNA synthesis >2-fold. In contrast to IL-8, CGRP did not induce monocyte chemotactic protein-1 or RANTES synthesis, nor did the neuropeptide enhance detectable increases in steady state levels of mRNA specific for these two beta-chemokines. The results suggest that HCEC possess CGRP receptors capable of initiating a signal transduction cascade that differentially activates expression of the IL-8 gene but not the genes for monocyte chemotactic protein-1 or RANTES. The capacity of CGRP to stimulate IL-8 synthesis in HCEC suggests that sensory neurons are involved in induction of acute inflammation at the eye surface.
Tran
M T
MT
Department of Microbiology/Immunology, College of Medicine, University of South Alabama, Mobile, AL 36688, USA.
Ritchie
M H
MH
Lausch
R N
RN
Oakes
J E
JE
D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism / Q000502:physiology*; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000096:biosynthesis / Q000235:genetics; D018946:Chemokine CCL5 / Q000096:biosynthesis / Q000235:genetics; D000242:Cyclic AMP / Q000096:biosynthesis; D019573:Epithelium, Corneal / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D016209:Interleukin-8 / Q000096:biosynthesis* / Q000235:genetics; D009475:Neurons, Afferent / Q000276:immunology / Q000378:metabolism; D012313:RNA / Q000096:biosynthesis; D018015:Receptors, Calcitonin Gene-Related Peptide / Q000096:biosynthesis
D018932:Chemokine CCL2; D018946:Chemokine CCL5; D016209:Interleukin-8; D018015:Receptors, Calcitonin Gene-Related Peptide; D012313:RNA; D000242:Cyclic AMP; D015740:Calcitonin Gene-Related Peptide