Cytokine loops involving interferon-gamma and IP-10, a cytokine chemotactic for CD4+ lymphocytes: an explanation for the epidermotropism of cutaneous T-cell lymphoma?
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.
Sarris
A H
AH
Department of Hematology, University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.
Esgleyes-Ribot
T
T
Crow
M
M
Broxmeyer
H E
HE
Karasavvas
N
N
Pugh
W
W
Grossman
D
D
Deisseroth
A
A
Duvic
M
M
D000328:Adult; D000368:Aged; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism / Q000473:pathology*; D015815:Cell Adhesion Molecules / Q000502:physiology; D054357:Chemokine CXCL10; D019743:Chemokines, CXC; D002634:Chemotaxis, Leukocyte; D002648:Child; D016207:Cytokines / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D000078404:Epidermal Cells; D004817:Epidermis / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007106:Immune Sera; D007371:Interferon-gamma / Q000494:pharmacology / Q000502:physiology*; D015603:Keratinocytes / Q000378:metabolism*; D016410:Lymphoma, T-Cell, Cutaneous / Q000473:pathology / Q000503:physiopathology*; D008875:Middle Aged; D008954:Models, Biological; D009363:Neoplasm Proteins / Q000502:physiology*; D014411:Neoplastic Stem Cells / Q000502:physiology*; D009928:Organ Specificity; D011817:Rabbits; D011994:Recombinant Proteins / Q000494:pharmacology; D012751:Sezary Syndrome / Q000473:pathology / Q000503:physiopathology; D012878:Skin Neoplasms / Q000473:pathology / Q000503:physiopathology*
D015815:Cell Adhesion Molecules; D054357:Chemokine CXCL10; D019743:Chemokines, CXC; D016207:Cytokines; D007106:Immune Sera; D009363:Neoplasm Proteins; D011994:Recombinant Proteins; D007371:Interferon-gamma