Hapten-specific tolerance promoted by calcitonin gene-related peptide.
Calcitonin gene-related peptide has been shown to modulate inflammatory and immune responses in various systems. Recent studies in our laboratory and colleagues have shown that intracutaneously injected calcitonin gene-related peptide impairs the induction of contact hypersensitivity in mice, and participates in the pathogenesis of failed contact hypersensitivity induction after acute, low-dose ultraviolet B radiation. In this study we investigated the ability of calcitonin gene-related peptide to induce tolerance in normal and mast cell deficient mice and we examined the extent to which calcitonin gene-related peptide contributes to the tolerance induced by acute, low-dose ultraviolet B radiation. Calcitonin gene-related peptide was injected intradermally followed by application of 2,4-dinitro-1-fluorobenzene to the injected skin surface. Tolerance was assessed by re-exposing the mice 2 wk later to a second, sensitizing dose of 2, 4-dinitro-1-fluorobenzene on uninjected skin. We found that calcitonin gene-related peptide induced tolerance to 2, 4-dinitro-1-fluorobenzene in both normal and mast cell deficient mice. Calcitonin gene-related peptide-induced tolerance was blocked by intradermal injection of a calcitonin gene-related peptide antagonist [CGRP-(8-37)] that selectively blocks the calcitonin gene-related peptide receptor. Tolerance was also abolished by intraperitoneally injected anti-interleukin-10, but not anti-tumor necrosis factor alpha, antibodies. When 2,4-dinitro-1-fluorobenzene was painted on skin into which splenic dendritic cells pretreated with calcitonin gene-related peptide had been injected, tolerance was observed. Calcitonin gene-related peptide- treated dendritic cells mixed with anti-interleukin-10 antibody prior to intradermal injection failed to promote tolerance. Finally, injection of CGRP-(8-37) into skin that was subsequently exposed to acute, low-dose ultraviolet B radiation partially prevented tolerance induced by local application of 2,4-dinitro-1-fluorobenzene. These results indicate that calcitonin gene-related peptide has the capacity to promote cutaneous tolerance through an interleukin-10-dependent mechanism. This mechanism, which does not require the participation of mast cells, contributes to the tolerance promoted by acute, low-dose ultraviolet B radiation. Thus, calcitonin gene-related peptide from cutaneous nerve endings plays a key role in the local immune aberrations caused by ultraviolet B radiation.
Kitazawa
T
T
Schepens Eye Research Institute, Harvard Medical School, Boston, Massachusetts 02114, USA.
Streilein
J W
JW
D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000494:pharmacology*; D003713:Dendritic Cells / Q000166:cytology; D000939:Epitopes; D005260:Female; D006241:Haptens / Q000276:immunology*; D007108:Immune Tolerance / Q000187:drug effects / Q000528:radiation effects; D016753:Interleukin-10 / Q000494:pharmacology; D008407:Mast Cells / Q000166:cytology / Q000276:immunology; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014466:Ultraviolet Rays
D000939:Epitopes; D006241:Haptens; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D015740:Calcitonin Gene-Related Peptide