Pro-inflammatory cytokines upregulate the skin immunoreactivity for NGF, NT-3, NT-4 and their receptor, p75NTR in vivo:: a preliminary report

Skin and hair follicles are both source and target of various cytokines and neurotrophins (NTs). While several pro-inflammatory cytokines are recognized to alter the expression of NTs and their receptors (NTRs), for example, on brain cells and fibroblasts in vitro, it is unknown whether this also occurs in normal mammalian skin in vivo. As a first step toward exploring this, we studied in murine back skin (C57BL/6) whether intradermally injected interleukin-1 beta (IL-1 beta), tumor necrosis factor-alpha (TNF-alpha), and interferon-gamma (IFN-gamma) altered the cutaneous immunoreactivity patterns of nerve growth factor (NGF), brain-derived neurotrophic factor ( BDNF), neurotrophin-3 (NT-3), neurotrophin-4 (NT-4), Trk-A, Trk-B, Trk-C and p75NTR and their receptors ( TrkA, TrkB, TrkC, p75NTR) on the protein level in situ. By immunohistology, IFN gamma, IL-1 beta, and TNF-alpha as well as a cocktail of all three cytokines increased NGF immunoreactivity (IR) in the proximal outer root sheath and hair matrix of anagen VI pelage hair follicles. The cytokine cocktail upregulated NT-3 and NT-4 IR in the epidermis, increased NT-4 IR in selected cells of the proximal outer root sheath, and also enhanced IR of p75NTR, in the follicular dermal papilla. Therefore, this pilot study provides the first preliminary indications that proinflammatory cytokines upregulate the cutaneous immunoreactivity of NGF, NT-3, NT-4 and their receptor p75NTR in vivo. This raises the question to which extent several of the recognized cutaneous effects of IFN gamma, IL-1 beta and TNF-alpha are mediated indirectly via modulating the expression of selected NTs and/or NTRs.