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Published online before print April 3, 2008

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(Journal of Leukocyte Biology. 2008;84:191-198.)
© 2008 by Society for Leukocyte Biology

Diminishment of -MSH anti-inflammatory activity in MC1r siRNA-transfected RAW264.7 macrophages

Schepens Eye Research Institute and the Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA

¹Correspondence: Schepens Eye Research Institute, 20 Staniford Street, Boston, MA 02114, USA. E-mail: andrew.taylor{at}schepens.harvard.edu

The neuropeptide -melanocyte-stimulating hormone (-MSH) is a powerful suppressor of inflammation mediated by macrophages, which express at least two receptors, melanocortin 1 and 3 receptors (MC1r and MC3r) that bind -MSH. Albeit, the anti-inflammatory activity of -MSH has been well documented in macrophages, the mechanisms of -MSH activity in macrophages are not clearly understood. This study is to investigate which of the MCr expressed on macrophages is associated with the immunosuppressive activities of -MSH on LPS-stimulated macrophages. To address this question, we transfected RAW264.7 macrophage cells with MC1r small interfering (si)RNA, which specifically targets mouse MC1r mRNA. The diminution of MC1r mRNA expression was 82% at 24 h and 67% at 48 h after transfection. There was a significant loss in -MSH suppression of NO generation and TNF- production by MC1r siRNA-transfected macrophages stimulated with LPS. There was an equally diminished -MSH suppression of LPS-stimulated intracellular activation of NF-B and p38 phosphorylation. In addition, the diminishment of MC1r expression by siRNA transfection had no influence on MC3r expression and function in the macrophages. These findings demonstrate that -MSH suppression of LPS-induced inflammatory activity in macrophages requires expression of MC1r. The results imply that although all of the MCr are G-coupled proteins, they may not necessarily function through the same intracellular pathways in macrophages.

Key Words: neuroimmunomodulation • immunosuppression • neuroimmunology • neuropeptides • inflammation • innate immunity