Heterotrimeric complex of p38 MAPK, PKCδ, and TIRAP is required for AP1 mediated inflammatory response

Mirza S. Baig, Dongfang Liu, Kannan Muthu, Anjali Roy, Uzma Saqib, Adnan Naim, Syed M. Faisal, Mansi Srivastava, Rohit Saluja

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

Inflammation could be described as a physiological response of the body to tissue injury, pathogen invasion, and irritants. During the inflammatory phase, cells of both the innate as well as adaptive immune system are activated and recruited to the site of inflammation. These mediators are downstream targets for the transcription factors; activator protein-1 (AP1), nuclear factor kappa-light-chain-enhancer (NF-κB), signal transducers and activators of transcription factors (STAT1), as well as interferon regulatory factors (IRFs), which control the expression of most immunomodulatory genes. There is a significant increase in active p38 mitogen-activated protein kinase (p38MAK) immediately after lipopolysaccharide (LPS) stimulation, which results in the activation of AP-1 transcription factor and expression of proinflammatory cytokines, IL-12 and IL-23. We studied the novel mechanism of p38 MAPK activation through the formation of a heterotrimeric complex of Protein kinase C delta type (PKCδ), Toll-Interleukin 1 Receptor (TIR) Domain Containing Adaptor Protein (TIRAP), and p38 proteins. TIRAP serves as an adaptor molecule which brings PKCδ and p38 in close proximity. The complex facilitates the activation of p38MAPK by PKCδ. Therefore, we propose that disruption of the heterotrimeric complex may be a good strategy to dampen the inflammatory response. Structure-based design of small molecules or peptides targetting PKCδ-TIRAP or TIRAP-p38 interfaces would be beneficial for therapy in AP1 mediated inflammatory diseases.

Original languageEnglish (US)
Pages (from-to)211-218
Number of pages8
JournalInternational Immunopharmacology
Volume48
DOIs
StatePublished - Jul 1 2017
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology
  • Pharmacology

Keywords

  • Activator protein-1 (AP1)
  • Heterotrimeric complex
  • Inflammation
  • Macrophage
  • Protein kinase C delta type (PKCδ)
  • p38 mitogen-activated protein kinase (p38MAPK)

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