Cytokine loops involving interferon-gamma and IP-10, a cytokine chemotactic for CD4+ lymphocytes: an explanation for the epidermotropism of cutaneous T-cell lymphoma? [see comments]

Abstract

Human interferon-gamma (IFN-gamma)-inducible protein 10 (IP-10), a C-X- C chemokine, is secreted by IFN-gamma-stimulated keratinocytes and is chemotactic for CD4+ lymphocytes. We therefore investigated its role in the epidermotropism of cutaneous T-cell lymphoma (CTCL) that is known to express IFN-gamma mRNA in the epidermis and is characterized by an indolent course with multiple relapses that remain confined to the skin for many years. By injecting purified recombinant (r) IP-10 we generated a polyclonal rabbit antiserum that specifically recognized and neutralized rIP-10. With immunoperoxidase staining, IP-10 expression was limited to the basal epidermal keratinocytes of normal skin. In biopsies of CTCL lesions the expression of IP-10 was markedly increased and it extended to the suprabasal keratinocytes in 17 of 18 patients, but it was detectable only faintly in the dermal or epidermal lymphoid infiltrates in 2 of these 18 patients. In 1 patient who had matching biopsies performed before and after treatment, IP-10 was overexpressed before treatment, but was normally expressed in the posttreatment biopsy that showed resolution of the CTCL. Increased IP- 10 expression was not detected in any of 4 patients with B-cell lymphoma involving the dermis. On the basis of these findings and a review of the literature, we propose that secretion of IFN-gamma by the lymphoid infiltrate in CTCL induces the epidermal keratinocytes to secrete IP-10 that, in turn, is chemotactic for CTCL, accounting for its epidermotropism. This model may be used as a basis for future investigations of the pathogenesis of CTCL.

Human IP‐10 selectively promotes dominance of polyclonally activated and environmental antigen‐driven IFN‐γ over IL‐4 responses

“…Note, however, that all studies to date have identified and visualized IP-10 as a downstream molecule induced by IFN-g directly or subsequent to IL-12 activity. Thus, Sarris et al (36) proposed that the interaction between IFN-g produced by lymphoma cells and IP-10 by keratinocytes was responsible for epidermotropism of CTCL cells. Based on the present study, where IP-10 clearly promotes strong IFN-g gene expression by antigen or polyclonally stimulated cells, we propose the existence of a positive amplification loop between IP-10 and IFN-g in vivo.…”

Cytokine expression patterns distinguish HIV associated skin diseases

“…IP-10 staining was diffuse and not localized to focal keratinocytes. It was similar in intensity and pattern to IP-10 staining in the epidermis of psoriasis (24) and mycosis fungoides (17,25,26). IP-10 is hypothesized to recruit and stimulate helper T cells.…”

Maternal serum concentrations of the chemokine CXCL10/IP-10 are elevated in acute pyelonephritis during pregnancy

“…CXCL10/IP-10 gene and protein expression is modulated by pro-inflammatory stimuli. Indeed, IFNγ is an inducer of the gene and protein expression of this chemokine by mononuclear cells [28], neutrophils [36,37], eosinophils [37,72], keratinocytes [28,31,32,34], fibroblasts [28], endothelial cells [28][29][30], pancreatic βcells [38,39], and animal astrocytes/microglia [33,35]. TNFα [37,[40][41][42][43][44][45][46], Interleukin (IL-1β) [37,38], as well as viral [33,48,49] and microbial products [37,47,[50][51][52], can also stimulate the production of IP-10.…”

“…IP-10 is inducible by pro-inflammatory stimuli such as interferon-γ (IFN-γ) [28][29][30][31][32][33][34][35][36][37][38][39], tumor necrosis factor-α (TNF-α) [37,[40][41][42][43][44][45][46] viruses, and microbial products [33,37,[47][48][49][50][51][52], either directly or through NF-kB [48,49,[53][54][55][56]. It has been proposed that this chemokine is also involved in the recruitment and potentiation of T-helper 1 (Th1) responses [57][58][59].…”