Cytokine response modifier A

Dbaibo, G.S., Perry, D.K., Gamard, C.J., and Hannun, Y.A., 1997, Cytokine response modifier A (CrmA) inhibits ceramide formation in response to tumor necrosis factor (TNF)-a CrmA and Bcl-2 target distinct components in the apoptotic pathway. J.Exp.Med. 185 481-490. 

Apart from lAPs, there are several nonmammalian regulators of caspases, which are active-site specific inhibitors (Callus and Vaux, 2007). One example is a serpin from the cowpox virus, cytokine response modifier A (crmA). CrmA forms a covalent complex with the initiator caspase-1 and -8 resulting in irreversible inhibition of these caspases. It also inhibits caspase-6 but less efficiently (Dobo et al., 2006). The baculoviral protein p35 is a broad spectrum caspase inhibitor that irreversibly inactivates caspases (Bump et al., 1995 Fisher et al., 1999). 

The first apoptotic inhibitor identified was a viral cross-class cysteine and serine protease inhibitor isolated from Cowpox virus, called Cytokine response modifier A (CrmA) or Serine protease inhibitor-2 (Spi-2). CrmA will be described in greater detail in a later section of this... 

Srikanth S, Kraft AS. Inhibition of caspases by cytokine response modifier A blocks androgen ablation-mediated prostate cancer cell death in vivo. Cancer Res 1998 58 834-839. 

A completely different example of the serpin CrmA (cytokine response modifier A), which expresses Cowpox virus. The targets of CrmA are members of the caspase family of proteases that either initiate the extrinsic pathway of apoptosis (caspases 8 and 10) or trigger activation of the pro-inflammatory cytokines interleukin-1 p and interleukin-18 (caspase 1). CrmA has the typical fold of a cleaved serpin, even though it lacks the N-terminal half of the A helix, the entire D helix, and a portion of the E helix that are present in all other known serpins. Thus, the inhibitory proteins can be not only drugs. They may also viral countermeasures to host defenses against infection may contribute significantly to the pathology associated with poxvirus infections (Renatus et al, 2000). 

The baculoviral protein p35 blocks apoptosis in insect cells and in neurons, but the site of action of this protein is not known (Clem et al., 1991 Rabi-zadeh et al., 1993a Martinou et al., 1995). The cowpox viral gene crmA (cytokine response modifier gene A) encodes a serine protease inhibitor (SERPIN)-like protein that is a specific inhibitor of ICE (Ray et al., 1992 Komiyama et al., 1994). CrmA protein inhibits the activity of ICE and the production of mature IL-ly3, thereby suppressing immune responses to infection (Ray et al., 1992 Komiyama et al., 1994). Microinjection of CrmA protein into cells prevents cell death in a number of systems including Fas-induced apoptosis (Enarl et al., 1995 Los et al., 1995 Tewari and Dixit ... 

Cytokines and biological response modifiers represent a broad class of therapeutic agents that modify the hosts response to cancer or cancer therapies. The enormous body information about their clinical uses and their side effects is beyond the scope of this essay that can only give illustrative examples. For an up-to-date information the reader can resort to reference [5]. As many as 33 different interleukins are known and the list continues to grow IL-2 used in the treatment of kidney cancer is one example. Interferon alpha is used for chronic myelogenous leukeia, hairy cell leukaemia and Kaposi s sarcoma. Interferons are also used in the treatment of chronic infections such as viral hepatitis. Tumor necrosis factor (alpha), G/GM/M-CSF, and several other cellular factors are used in treatment of various cancers. Many of these cytokines produce serious side effects that limit their use. 

Recently, it has been shown that inhalation of MWNTs caused suppression of the systemic immunity without resulting in significant lung inflammation or tissue damage [82,83]. Inhaled MWNTs in fact modified the functionality of spleen cells in exposed mice [82]. Notably, the activity of cyclooxygenase (COX) enzymes in spleen was affected as a response to a cytokine (TGF(5) released from the lungs. This cytokine activated the COX pathway in the spleen, triggering T-cell dysfunction and systemic immunosuppression [83]. 

CN187 Sadeghi, S., F. A. Wallace, and P. C. Calder. Dietary lipids modify the cytokine response to bacterial lipo-polysaccharide in mice. Immunology 1999 96(3) 404-410. 

Activation of CD4 T// ceiis. (a) CD4 T// ceiis recognize antigen presented on MHC ciass ii moiecuies. Co-stimuiation and autocrine signaiing are required to compiete activation and drive cionai expansion, (b) Activated CD4 T// ceiis may proiiferate into either T//- or T//2 ceiis. (c) and T//2 ceiis secrete a variety of cytokines that stimuiate the generation of either ceiiuiar or humorai immune responses. (Modified from Janeway et ai. [38] Figure 8.10)... 

IL-2 and IL-15, which uses the (3- and y-chains of the IL-2R, have been found in melanoma cells and anti-IL-15 mAbs to inhibit HLA class I expression in these cells. Therefore these cytokines may modify the behavior of both stromal and neoplastic cells inside a tumor. These data may have important implications for our understanding of tumor-host interactions and in future strategies of immunotherapy. When compared with lL-2, which enhances both spontaneous and antigen-induced lymphocyte proliferative responses, IL-15 rarely increases spontaneous lymphocyte proliferation. Thus IL-15 may help to correct the impaired profiferative response of CD4 lymphocytes from HlV-l-infected persons without the mitogenic effect of IL-2, which also may induce HIV-1 expression. "... 

Elsasser-Beile U, von Kleist S, Lindenthal A, Birken R, Gallati H, Monting JS (1993) Cytokine production in whole blood cell cultures of patients undergoing therapy with biological response modifiers or 5-fluorouracil. Cancer Immunol Immunother 37 169-174... 

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