SHORT COMMUNICATION Holger Bla¨sing Æ Sven Hendrix Æ Ralf Paus Pro-inflammatory cytokines upregulate the skin immunoreactivity for NGF, NT-3, NT-4 and their receptor, p75NTR in vivo: a preliminary report Received: 14 March 2005 / Accepted: 17 March 2005 / Published online: 5 May 2005 Ó Springer-Verlag 2005 Abstract Skin and hair follicles are both source and target of various cytokines and neurotrophins (NTs). While several pro-inflammatory cytokines are recog- nized 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-1b (IL-1b), tumor necrosis factor-a (TNF-a), and interferon-c (IFN-c) al- tered 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 recep- tors (TrkA, TrkB, TrkC, p75NTR) on the protein level in situ. By immunohistology, IFNc, IL-1b, and TNF-a 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 IFNc, IL-1b and TNF-a are mediated indirectly via modulating the expression of selected NTs and/or NTRs. Keywords Interleukin À1b Æ Tumor necrosis factor-a Æ Interferon-c Æ Hair follicle Æ Skin There is increasing evidence that neurotrophins (NTs) and pro-inflammatory cytokines play a major role in hair follicle development, growth and regression as well as in skin and hair diseases [1–5, 14, 22]. However, the interplay of cytokines and NTs in skin and hair follicles in vivo is still obscure. Neurotrophins are a family of closely related poly- peptides first described for their effects on the central and peripheral nervous systems. The main members are nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-4 (NT-4) and neurotro- phin3 (NT3). Their receptors are Trk-A (NGF), TrkB (NT4, BDNF), Trk-C (NT-3) and p75NTR [7]. Interferon-c (IFN-c), interleukin-1b (IL-1b) and tu- mor necrosis factor-a (TNF-a) are potent hair growth inhibitors and important pro-inflammatory cytokines, and increased levels of IFN-c and IL-1b have, for example, been detected in untreated alopecia areata le- sions [14, 22]. Several in vitro studies indicate that var- ious cytokines are able to modulate the expression of NTs in astrocytes and Schwann cells [8, 15, 16, 18], mesangial cells [23, 29] and fibroblasts [12, 13]. However, it is not yet known whether and how these prototypic pro-inflammatory cytokines, which play a critical role both in the normal skin immune system and in the pathogenesis of a wide range of inflammatory and hy- perproliferative skin diseases [1], interfere with cutane- ous NT expression and neurotrophin-receptor (NTR)- mediated signaling in mammalian skin in vivo. The C57BL/6 mouse model offers an excellent tool for studying the in vivo regulation of NT and NTR expression in mammalian skin, since murine hair folli- cles are important targets and sources not only for Holger Bla¨sing and Sven Hendrix have contributed equally. H. Bla¨sing Æ R. Paus (&) Department of Dermatology, University Hospital Eppendorf, Hamburg University, Martinistraße 52, 20246 Hamburg, Germany E-mail: paus@uke.uni-hamburg.de Tel.: +49-40-428033637 Fax: +49-40-428036744 S. Hendrix Center for Anatomy, Institute of Cell Biology and Neurobiology, Charite´ University Hospital, Schumannstr. 20-21, 10098 Berlin, Germany Arch Dermatol Res (2005) 296: 580–584 DOI 10.1007/s00403-005-0563-y