T cells expressing allograft inflammatory factor 1 display increased chemotaxis and induce a profibrotic phenotype in normal fibroblasts in vitro.
OBJECTIVE
Allograft inflammatory factor 1 (AIF-1) was first identified in rat cardiac allografts undergoing chronic rejection. The vasculopathy of chronic allograft rejection is strikingly similar to that seen in patients with systemic sclerosis (SSc). We previously demonstrated AIF-1 expression in inflammatory cells infiltrating skin and lungs from SSc patients, but its role in SSc pathogenesis is unknown. The present study was undertaken to investigate the effects of AIF-1 on T cell migration and production of cytokines capable of modulating normal dermal fibroblast functions.


METHODS
Stably transfected Jurkat T cells expressing 2 AIF-1 splicing variants were prepared, and their migration toward fibroblast monolayers assayed in Transwell cultures. Cytokine production was assessed by real-time polymerase chain reaction (PCR) and multiplex enzyme-linked immunosorbent assay. Fibroblast gene expression was quantified by real-time PCR, and collagen production by Western blot analysis of culture media.


RESULTS
AIF-1 significantly increased Jurkat T cell migration toward fibroblast monolayers. Expression of AIF-1 isoform 2 in Jurkat T cells up-regulated their production of interleukin-4 (IL-4) and IL-17. Conditioned media from AIF-1-expressing clones stimulated synthesis of types I and III collagen and expression of IL-6, transforming growth factor beta, endothelin receptor, and alpha-smooth muscle actin by normal dermal fibroblasts.


CONCLUSIONS
These results suggest that AIF-1 may participate in the early pathogenesis of SSc by promoting tissue T cell infiltration and production of cytokines capable of inducing the expression of a fibrotic phenotype in normal fibroblasts.
Del Galdo
Francesco
F
Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
Jiménez
Sergio A
SA
D000818:Animals; D015153:Blotting, Western; D002135:Calcium-Binding Proteins; D002465:Cell Movement / Q000502:physiology; D002633:Chemotaxis / Q000502:physiology*; D016207:Cytokines / Q000096:biosynthesis*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005347:Fibroblasts / Q000378:metabolism*; D015870:Gene Expression; D006801:Humans; D066298:In Vitro Techniques; D020381:Interleukin-17; D015847:Interleukin-4; D019169:Jurkat Cells; D008840:Microfilament Proteins; D010641:Phenotype; D016133:Polymerase Chain Reaction; D012595:Scleroderma, Systemic / Q000209:etiology; D013601:T-Lymphocytes / Q000378:metabolism*; D015854:Up-Regulation
C112986:AIF1 protein, human; D002135:Calcium-Binding Proteins; D016207:Cytokines; D004268:DNA-Binding Proteins; D020381:Interleukin-17; D008840:Microfilament Proteins; D015847:Interleukin-4