IL-6 and b-FGF Overproductions Precede Development of AIDS-Associated Kaposi's Sarcoma (1996)

To the Editor: Important progress has been made in the last 2 years to understand the pathogenesis of AIDS-associated Kaposi's sarcoma (KS) but in vivo correlations are still lacking in humans. The actual model of pathogenesis implies a herpes virus and a situation of cytokine imbalance (1,2). Several growth factors like Oncostatin M (OSM), Platelet Derived Growth Factor (PDGF), basic Fibroblast Growth Factor (b-FGF), and Interleukin-6 (IL-6) have been shown capable of promoting the growth of KS cells in vitro or of inducing vascular lesions closely resembling those of KS after inoculation in mice (3-6). We present here the first evidence that at least two of these cytokines are overproduced in vivo several months before the development of clinical lesions in AIDS-associated KS. Serum levels of OSM, PDGF, b-FGF, and IL-6 were measured on samples stored at -70°C with commercially available ELISA kits (R & D Systems, Minneapolis, MN, U.S.A.). Ten homosexual men without HIV-1 infection were used as controls. The HIV-1-infected population included 23 homosexual men evaluated only at the time when KS was diagnosed, 16 homosexual men evaluated at the time of KS diagnosis and 1 year before, and 14 homosexual men with same mean age and CD4+ T cells count that did not develop KS with a mean follow-up of 36 months. All evaluations were done in the absence of concomitant infections able to induce increased production of some cytokines. No statistically significant difference was found for these four cytokines in serum between HIV-negative homosexual men and HIV-positive men that did not develop KS. Mean ± SEM levels were statistically higher in the 39 HIV-positive patients at the first time KS was diagnosed than in the 14 HIV-positive patients that did not develop KS for IL-6 (13.32 ± 2.13 pg/ml vs. 2.49 ± 0.75 pg/ml; Mann Whitney test, p < 0.001) and b-FGF (6.01 ± 0.96 pg/ml vs. 2.16 ± 0.51 pg/ml; Mann Whitney test, p = 0.01) but not for OSM or PDGF. Increased IL-6 and b-FGF levels were present at least 1 year before the first cutaneous lesion of KS was found in the group of 16 patients with available pre-KS serum (Table 1). IL-6 and b-FGF levels increased further with development of KS (Wilcoxon test, p = 0.03) in these 16 patients. b-FGF and IL-6 are essential for growth of KS cells and are not only produced by KS cells themselves but also endogenously by a large variety of cells (2,5,6). Our study demonstrates that these two factors are closely associated in vivo with KS development and are increased in serum of patients several months before KS is clinically detectable. Because none of our patients presented evidence of visceral involvement by KS during follow-up, it is noteworthy that these increased levels found 1 year before were the result of production by occult KS lesions. On the contrary, we think that these increased levels can provide an appropriate milieu for the subsequent development of KS lesions. As elevated levels of IL-6 (7) and perhaps b-FGF remain not specific for KS, prospective studies are necessary to determine if early monitoring of this increased production could help detect patients at high risk for KS, in particular in association with other possible factors such as a positive PCR detection of KSHV (8). Nevertheless, as conventional therapies of AIDS-associated KS are often disappointing (9), early interventions aimed at modifying this cytokine imbalance should be evaluated (10,11). Acknowledgment: This work has been funded by a grant from the Agence Nationale de Recherche sur le SIDA (ANRS). *Alain Lafeuillade; †Gilles Kaplanski; ‡Thierry Allegre; §Jean Pierre de Jaureguiberry *Department of Infectious Diseases; General Hospital §Department of Hematology; Army Teaching Hospital; Toulon, France †Laboratory of Immunology; University Hospital; Marseille, France ‡Department of Hematology; General Hospital; Aix en Provence, France