T helper type 1 cytokines and keratinocyte growth factor play a critical role in pseudoepitheliomatous hyperplasia initiation during cutaneous leishmaniasis

Abstract

Pseudoepitheliomatous hyperplasia (PEH) is an exuberant proliferation of the epidermis. The underlying mechanism(s) that lead to PEH have not been completely elucidated. Here, we characterize PEH during the healing stages of cutaneous leishmanial ulcers in mice. During experimental cutaneous leishmaniasis (CL) C57BL/6 mice produce PEH, and BALB/c do not. A series of immunohistochemical and immunological studies were performed to identify the secretory products of PEH regulation. We observed that the distribution of TNF-alpha and IFN-gamma under PEH had a stripe-like diffuse pattern and localized in the upper part of the papillary dermis directly under the proliferating epidermis. Macrophages were identified as the major source of TNF-alpha (56.3%). The importance of IFN-gamma and TNF-alpha in PEH development was proven by the initiation of PEH after three intralesional injections of TNF-alpha and IFN-gamma every three days in infected BALB/c mice. In C57BL/6 mice, keratinocyte growth factor (KGF) expressing cells were found immediately under the basal membrane of the hyperplastic epidermis in comparison with sporadic KGF positive cells deep in the dermis of BALB/c mice. Quantitative RT-PCR analysis demonstrated increased KGF and KGF receptor expression in uninfected C57BL/6 mice as compared to BALB/c mice. These data indicate that Th1 cytokines and KGF play a critical role in PEH initiation during CL.

Increased prevalence of bisphosphonate-related osteonecrosis of the jaw with vitamin D deficiency in rats

“…(30) Akilov and colleagues (2007) demonstrated in the experimental cutaneous leishmaniasis mouse model that intralesional injections of TNF-α and IFN-γ initiated PEH in mouse ear skin. (31) The upregulation of TNF-α and IFN-γ in postextraction oral mucosa of the VitD(−)/ZOL group (Fig. 4) appears to provide a pathologic mechanism to develop PEH in our model.…”

Immunohistochemical profile of cytokeratins in pseudoepitheliomatous hyperplasia of cutaneous Leishmaniasis

“…The evaluation of Ck immunolabeling in PEH was performed exclusively in a previous study with paracoccidioidomycosis oral samples 11 . Microscopically, CL could present PEH 5 . The origin of PEH is unknown; however, it might be an adaptive process of squamous metaplasia of the eccrine gland or reactive epithelium proliferation associated with the underlying chronic inflammation 6,12 .…”

“…CL is not contagious, with a chronic evolution which affects the skin and cartilaginous structures of the nasopharynx, with localized or diffuse presentation 4 . Leishmania spp., microscopically, cause pseudoepitheliomatous hyperplasia (PEH) 5 . PEH is characterized by hyperplasia of the epithelium with irregular expansion and downgrowth of rete pegs into the connective tissue that may mimic a well‐differentiated squamous cell carcinoma, and it might lead to erroneous diagnosis and inappropriate treatment 6 .…”

“…PEH is characterized by hyperplasia of the epithelium with irregular expansion and downgrowth of rete pegs into the connective tissue that may mimic a well‐differentiated squamous cell carcinoma, and it might lead to erroneous diagnosis and inappropriate treatment 6 . The underlying mechanisms that lead to PEH have not been completely elucidated 5 . Keratins are the predominant cytoskeletal protein of stratified keratinized epithelial cells and are the most sensitive markers of epithelial differentiation and proliferation 7–9 .…”

Pseudocarcinomatous Hyperplasia Associated With Hidradenoma Papilliferum

“…Cutaneous pseudocarcinomatous hyperplasia is a benign proliferation that can be associated with many nontumoral conditions [1][2][3][4][5][6] and with several types of tumors [7][8][9][10][11][12][13][14] (Table 1). Awareness of these associations is crucial to prevent misdiagnosis of this type of proliferation as a verrucous or squamous cell carcinoma (SCC).…”