The development of an effective immune response following infection with a pathogen plays a critical role in determining the susceptibility or resistance of the host to the pathogen. Over the course of the infection, activated naïve CD4+ and CD8+ T cells proliferate and differentiate into effector cells that in turn promote clearance of the pathogen. Naïve CD4+ T cells differentiate into effector T helper (Th 1 or Th 2) cells that produce large amounts of cytokines. Effector Th 1 cells produce primarily interferon-γ (IFNγ ) and promote cell-mediated immunity, while Th 2 cells secrete interleukin IL-4, IL-5 and IL-10 to promote humoral immunity. Naïve CD8+ T cells differentiate to effector cytoxic T cells that also secrete high levels of IFNγ in response to antigen and promote the defense against cytosolic pathogens.
During these processes, a substantial reprogramming of gene expression occurs. The transcription factors that regulate the expression of the genes and the signalling pathways that control the activity of the transcription factors play an essential role in the development of an effective immune response and subsequently disease progression. Signal transduction via MAP kinases are involved in a variety of cellular responses, including growth factor induced proliferation, differentiation and cell death. Several parallel MAP kinase signal transduction pathways have been defined in mammalian cells. These pathways include the extracellular signal related kinases (ERKs), c-Jun amino terminal kinases (JNK) (also known as SAPK) and p38 MAP kinases. These MAP kinase groups are functionally independent and have been implicated in different biological processes. The ERK signalling pathway is induced by growth factors and has been primarily associated with proliferation, while the JNK and p38 MAP kinase signalling pathways are activated by stress and cytokines, and have been involved in cell death and differentiation.
Three JNK genes have been identified, Jnk1, Jnk2 and Jnk3. Jnk1 and Jnk2 are constitutively expressed in a large variety of tissues except in spleen and lymph nodes, where both Jnk1 and Jnk2 genes expression is induced after in vivo and in vitro activation. Mice deficient for Jnk2 have impaired IFNγ production and CD4+ Th 1 differentiation, whereas CD4+ T cells from the Jnk1 deficient mice produce more Th 2 type cytokines. In contrast, the ERK signalling pathway is required for Th 2 differentiation.
P38 MAP kinase can be activated by multiple stimuli, such as proinflammatory cytokines (IL-1 β and tumor necrosis factor-α (TNFα )), some hematopoietic growth factors (colony stimulating factor-1, granulocyte macrophage-colony stimultating factor and IL-3), lipopolysaccharide and environmental stress (heat, osmotic stress, UV irradiation). The p38 MAP kinase is activated by the MAP kinase kinases MKK3, MKK4 and MKK6. These MAP kinase kinases phosphorylate p38 MAP kinase on Thr and Thr within the tripeptide motif TGY in kinase subdomain VIII, thereby increasing enzymatic activity. p38 MAP kinase phosphorylates and activates ATF2, E1k-1, CHOP, MEF2C and SAP-1 transcription factors. p38 MAP kinase also phosphorylates and activates the eIF-4E protein kinases Mnk1, Mnk2 and the small heat shock protein hsp27 protein kinase MAPKAP kinase-2.
p38 MAP kinase has been implicated in the expression of proinflammatory cytokines (e.g. IL-6 and TNFα ) and neuronal cell death. p38 MAP kinase plays an important role in the production of IFNγ by CD4+ Th 1 cells and CD8 + T cells in vitro.