Tissue injury, microbial infection, contact allergens, etc. provide danger signals, leading to a local production of proinflammatory cytokines that induce LC mobilization to the lymphoid tissue. At the same time, signals are generated to recruit LC precursors into the skin and maintain the epidermal LC population [
7]. It has been documented that the number of LCs in epidermis decreased in HPV infected skin [
16]. However, the significance of LCs populated in the skin under different conditions has been hotly debated. Fushimi T et al showed that CCL-20/MIP-3α transgene attracted dendritic cells to established murine tumors and suppressed tumor growth [
17]. Bonnotte et al [
18] indicated that the high density of DCs in the tumor site was not a sufficient condition to induce an immune response. Furthermore, this attraction of immature DCs may always have an adverse effect by inducing a tolerance to the tumor cells. We have recently demonstrated that local hyperthermia decreased the number of epidermal LCs in a temperature dependant manner, in both normal and HPV infected skin. It was also noted that expression of CCR-7 increased and CCR6, decreased on emigrated CD1a+ cells in temperature dependant manner [
6]. Hyperthermia induced immigration of LCs away from the epidermis were recovered in about one to two weeks [
19]. CCL-20 is a CC chemokine constitutively expressed in tissues such as liver, lung, follicle-associated epithelial cells. In skin, CCL-20 is mainly expressed in keratinocytes, skin fibroblast, microvascular endothelial cells and dendritic cells [
20,
21]. The ligand-receptor pair CCL20-CCR6 is responsible for the chemoattraction of immature dendritic cells, effector/memory T-cells and B-cells [
22]. CCL-20 was weakly expressed in normal human skin but was strongly augmented in some inflamed diseases, such as atopic dermatitis and psoriasis [
10,
11]. In vitro studies showed that following proinflammatory stimuli, both high- and low-risk HPV E6 and E7 inhibited CCL-20 transcription, resulting in suppression of the migration of immature Langerhans precursor- like cells [
23,
24]. The expression status of CCL20 in clinical specimen has not been documented. In the present study, we detected high expression of CCL20 mRNA in CA, as compared with normal skin, a result contradictory to the
in vitro observation. It was speculated that: (1) HPV E6 and E7 genes were not active in highly differentiated layers of epidermal keratinocytes; (2) uninfected keratinocytes or infected keratinocytes without HPV E6 and E7 expression produced CCL20 locally; (3) other cellular types, such as Langerhans cell, fibroblast, endothelial cells or infiltrating lymphocytes produced CCL20 locally. Local hyperthermia at 42°C and 45°C for 30 min reduced the mRNA expression of CCL20 to about 6- and 7- folds, respectively. We previous showed that local hyperthermia under certain condition was able to reduce the mRNA expression of CCR6 on immigrated CD1a+ Langerhans cells, and there was a concomitant decrease of epidermal LCs [
6]. As the ligand-receptor pair CCL20-CCR6 is responsible for the chemoattraction of immature dendritic cells to the epidermis, we conclude that instantaneous local hyperthermia is an unfavourable condition to attract LCs into epidermis, instead it provides a favourable milieu to drive LCs away from the epidermis. Paradoxically, local hyperthermia at 45°C increased CCL-20 mRNA to about 2.5 fold in normal skin, as compared with untreated specimens. The increase in expression was marginal and its significance needs further study.
It has been shown that upon stimulation with IL-1α and TNF-α, CCL-20 was produced by keratinocytes at high level [
10,
11]. In the present study, we observed concomitant decrease of IL-1α and CCL-20 in CA with concomitant increase of IL-1α and CCL-20 in normal skin. In addition, CCL-20 expression appeared to be positively correlated with IL-1α under hyperthermia conditions. Either in CA or in normal skin, TNF-α expression remained unchanged in spite of the hyperthermia conditions. The result was partly consistent with the finding by others [
25] that heating had no effect on the expression of TNF-α. Local hyperthermia affects several other cytokines. Zhu et al [
26] showed that hyperthermia at 42°C and 45°C was able to induce a significant increase in the transcriptional expression of IFN-α, IFN-β and IFN-γ, in a temperature-dependent manner in CA, but not in normal skin. The mechanisms of local hyperthermia were complicated. Different studies indicated that the combination of different pathway is probably contributory to eliminating the warts.