PPARgamma expression is increased in systemic lupus erythematosus patients and represses CD40/CD40L signaling pathway.

摘要

Systemic lupus erythematosus (SLE) is a heterogeneous disease involving several immune cell types and pro-inflammatory signals, including the one triggered by binding of CD40L to the receptor CD40. Peroxisome-proliferator activated receptor gamma (PPARgamma) is a transcription factor with anti-inflammatory properties. Here we investigated whether CD40 and PPARgamma could exert opposite effects in the immune response and the possible implications for SLE. Increased PPARgamma mRNA levels were detected by real-time PCR in patients with active SLE, compared to patients with inactive SLE PPARgamma/GAPDH mRNA = 2.21 +/- 0.49 vs. 0.57 +/- 0.14, respectively (p < 0.05) or patients with infectious diseases and healthy subjects (p < 0.05). This finding was independent of the corticosteroid therapy. We further explored these observations in human THP1 and in SLE patient-derived macrophages, where activation of CD40 by CD40L promoted augmented PPARgamma gene transcription compared to non-stimulated cells (PPARgamma/GAPDH mRNA = 1.14 +/- 0.38 vs. 0.14 +/- 0.01, respectively; p < 0.05). This phenomenon occurred specifically upon CD40 activation, since lipopolysaccharide treatment did not induce a similar response. In addition, increased activity of PPARgamma was also detected after CD40 activation, since higher PPARgamma-dependent transcription of CD36 transcription was observed. Furthermore, CD40L-stimulated transcription of CD80 gene was elevated in cells treated with PPARgamma-specific small interfering RNA (small interfering RNA, siRNA) compared to cells treated with CD40L alone (CD80/GAPDH mRNA = 0.11 +/- 0.04 vs. 0.05 +/- 0.02, respectively; p < 0.05), suggesting a regulatory role for PPARgamma on the CD40/CD40L pathway. Altogether, our findings outline a novel mechanism through which PPARgamma regulates the inflammatory signal initiated by activation of CD40, with important implications for the understanding of immunological mechanisms underlying SLE and the development of new treatment strategies.