In animal models, IL-12 and IL-23 participate in the development of malignant neoplasms of keratinocytes. However, the role of these cytokines in pigmented lesion development and their progression to melanoma has received little attention. IL-12p35, IL-23p19, and IL-12/IL-23p40 knockout mice on a C3H/HeN background, subjected to a melanomagenesis protocol, demonstrated profound differences in susceptibility to nevus initiation, transformation, tumorigenicity, and metastatic potential. IL-23 was found to be essential for melanocyte homeostasis, whereas IL-12 supported nevus development. A direct action of IL-23 on primary melanocytes, shown to be IL-23R+, demonstrated that DNA repair of damaged melanocytes requires IL-23. Furthermore, IL-23 modulated the cutaneous microenvironment by limiting regulatory T cells and IFN-γ and inhibiting IL-10 production. Neutralizing Ab to IFN-γ, but not IL-17, inhibited nevus development (p < 0.01).
↵2 L.T. and C.A.E. are coprincipal investigators.
This work was supported by Veterans Administration Grant 1I01BX003395 and National Cancer Institute Grant 1R01CA193885 (to C.A.E) and by University of Alabama at Birmingham Comprehensive Cancer Center Grant P30CA013148.
The online version of this article contains supplemental material.
Abbreviations used in this article:
- contact hypersensitivity
- N6,2′-O-dibutyryladenosine 3′,5′-cyclic monophosphate
- draining LN
- lymph node
- quantitative PCR
- squamous cell carcinoma
- University of Alabama at Birmingham
- Received August 23, 2016.
- Accepted November 16, 2016.
- Copyright © 2017 by The American Association of Immunologists, Inc.