Mechanisms of CD40-mediated Expression of MMPs &TIMP-1

Fred Hutchinson Cancer Research Center, Seattle WA

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Abstract

[unreadable] DESCRIPTION (provided by applicant): Obliterative bronchiolitis (OB) is a major factor limiting survival after lung transplantation. Abnormal expression of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) is observed in OB and likely plays a vital role in the obliteration of small airways. Our work in progress find that CD40 engagement on mouse lung fibroblasts selectively induces TIMP-1 and MMP-3 expression. Aim 1 is to characterize the mechanisms of CD40-mediated TIMP-1 expression on mouse lung fibroblasts. Studies will determine regulation of TIMP-1 expression at the transcriptional and post-transcriptional level after CD40 activation on fibroblasts. After CD40 ligation on fibroblasts, activator protein-1 and polyomavirus enhancer A3 promoter activity on the TIMP-1 gene will be determined as well as the relative roles of the JNK, p42/p44 and p38 MAPK signaling pathways in mediating TIMP-1 expression. Aim 2 is to characterize MMP expression after CD40 activation on lung fibroblasts. Protein and mRNA expression of MMP-3, MMP- 9, MMP-11, MMP-13 and MT1-MMP will be determined. Additionally, the role of the JNK, p42/p44 and p38 MAPK signaling pathways in MMP expression after CD40 activation on lung fibroblasts will be determined. [unreadable] [unreadable]