Interferon-inducible protein 10 as a possible factor in the pathogenesis of cutaneous T-cell lymphomas

• Published in: Clinical cancer research 1997-02, Vol.3 (2), p.169-177
• Main Authors: SARRIS, A. H, DALIANI, D, DEISSEROTH, A. B, DUVIC, M, ULMER, R, CROW, M, BROXMEYER, H. E, REISS, M, KARASAVVAS, N, ZELENETZ, A. D, PUGH, W, CABANILLAS, F
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Biological and medical sciences; Cell Division; Chemokine CXCL10; Chemokines, CXC - biosynthesis; Chemokines, CXC - physiology; Cytokines - metabolism; Female; Hematologic and hematopoietic diseases; Humans; Interferon-gamma - metabolism; Keratinocytes - metabolism; Keratinocytes - pathology; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Lymphoma, T-Cell, Cutaneous - etiology; Lymphoma, T-Cell, Cutaneous - pathology; Male; Medical sciences; Middle Aged; Skin Neoplasms - etiology; Skin Neoplasms - pathology
• ISSN: 1078-0432; 1557-3265

Human IFN-gamma-inducible protein 10 (IP-10), a C-X-C chemokine secreted by IFN-gamma-stimulated keratinocytes, is chemotactic for normal CD4-positive lymphocytes and inhibits the proliferation of early subsets of normal and of leukemic hemopoietic progenitors. Cutaneous T-cell lymphoma (CTCL) is an indolent lymphoproliferative disorder of CD4-positive lymphocytes that remain confined to the skin for many years before visceral dissemination. Because IFN-gamma mRNA was detected in the epidermis of CTCL lesions, we decided to investigate the role of IP-10 in the epidermotropism of CTCL by determining its expression in normal skin and in CTCL lesions. Using purified recombinant IP-10 (rIP-10) or a recombinant fusion protein between IP-10 and the straight phi10 protein of phage T7, we generated rabbit antisera that recognized and neutralized rIP-10. Immunoperoxidase staining of normal epidermis demonstrated that IP-10 was expressed by basal keratinocytes but not by the more differentiated cells. In the often hyperplastic epidermis overlying CTCL lesions, IP-10 immunostaining was enhanced compared to normal skin and extended to the suprabasal keratinocytes in 28 of 29 patients for a frequency of 97% and a 95% confidence interval of 82-100%. However, IP-10 was detectable in the dermal or epidermal lymphoid infiltrates in only 3 of 29 patients (10%; 95% confidence interval, 2-29%). Skin clinically free of CTCL demonstrated normal IP-10 immunostaining. In one patient who had matching biopsies performed before and after treatment, IP-10 was overexpressed before treatment but was normally expressed at remission. The in vitro proliferation of primary normal human keratinocytes was inhibited in a dose-dependent manner by rIP-10. These results suggest that IP-10 plays a role in the epidermotropism of CTCL. Additional work is needed to determine whether IP-10 stimulates or inhibits CTCL proliferation. A better understanding of the growth controls operating in CTCL may be useful in the development of curative strategies for this disorder.